Pharmaceutical compositions comprising meloxicam

ABSTRACT

Disclosed herein are compositions comprising an NSAID such as meloxicam and/or rizatriptan in combination with a cyclodextrin and/or a carbonate or a bicarbonate. These compositions may be orally administered, for example, to improve the bioavailability or pharmacokinetics of the NSAID for the treatment of pain such as migraine, arthritis, and other conditions. Also disclosed herein are methods of treating pain, such as migraine, comprising administering meloxicam and rizatriptan to a human being suffering from pain, such as migraine. For migraine, these methods may be particularly useful when the meloxicam and rizatriptan are administered while the human being is suffering from an acute attack of migraine pain or migraine aura. In some embodiments, the combination of meloxicam and rizatriptan may be administered in a manner that results in a T max  of meloxicam of 3 hours or less.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 16/693,052, filed Nov. 22, 2019; which is acontinuation-in-part of U.S. patent application Ser. No. 16/567,859,filed Sep. 11, 2019, now U.S. Pat. No. 10,517,950; which is acontinuation-in-part of U.S. patent application Ser. No. 16/006,548,filed Jun. 12, 2018, now U.S. Pat. No. 10,463,736; which is acontinuation of U.S. patent application Ser. No. 15/902,770, filed Feb.22, 2018, now U.S. Pat. No. 10,029,010; which is a continuation of U.S.patent application Ser. No. 15/797,955, filed Oct. 30, 2017, now U.S.Pat. No. 10,058,614; which is a continuation-in-part of U.S. patentapplication Ser. No. 15/132,130, filed Apr. 18, 2016, now U.S. Pat. No.9,821,075; which is a continuation of International Pat. App. No.PCT/US2016/026991, filed Apr. 11, 2016, which claims the benefit of U.S.Provisional Pat. App. Nos. 62/114,215, filed Feb. 10, 2015, and62/259,993, filed Nov. 25, 2015; U.S. patent application Ser. No.15/797,955 also claims the benefit of U.S. Provisional Pat. App. Nos.62/526,884, filed Jun. 29, 2017, and 62/536,466, filed Jul. 25, 2017;any of the above applications, U.S. patents issued from, or U.S.publications of any of the above applications are incorporated byreference in their entirety.

BACKGROUND

Meloxicam, which has the structure:

is a nonsteroidal anti-inflammatory (NSAID) drug that exhibitsanti-inflammatory, analgesic, and antipyretic activities. The meloxicammechanism of action may be related to prostaglandin synthetase(cyclo-oxygenase, COX) inhibition which is involved in the initial stepsof the arachidonic acid cascade, resulting in the reduced formation ofprostaglandins, thromboxanes and prostacylin.

SUMMARY

Meloxicam and some other NSAIDs have poor aqueous solubility which mayreduce bioavailability and slow the onset of pain relief resulting fromtheir use. One means of increasing the solubility and bioavailability ofmeloxicam is through the use of cyclodextrins. Cyclodextrin (also knownas cycloamyloses) are generally cyclic polysaccharides which form abucket-like shape. Cyclodextrins help to increase bioavailability ofother molecules because cyclodextrins are hydrophobic on the inside andhydrophilic on the inside which helps to facilitate the transport ofmolecules. The naturally occurring cyclodextrins include six, seven, andeight glucose units (α, β, and γ-cyclodextrin, respectively). However,synthetic cyclodextrins containing more or less glucose units arepossible. In aqueous solutions, cyclodextrins can form complexes (i.e.,an inclusion complex) with drugs by incorporating the drug into thecenter/hydrophobic portion of the cyclodextrin ring; althoughcyclodextrin compounds are also known to aggregate around a drug in amicelle-type structure. This ability of cyclodextrins may allow them toact as carriers to increase the bioavailability of less soluble drugs.

Some embodiments include a method of treating migraine comprising:selecting a human migraine patient with a history of inadequate responseto prior migraine treatments, and orally administering a dosage form tothe migraine patient, wherein the dosage form comprises a combinationof: 1) a complex of meloxicam with a sulfobutyl ether β-cyclodextrin(SBEβCD), 2) a bicarbonate, and 3) a rizatriptan.

Some embodiments include an inclusion complex of meloxicam in acyclodextrin.

Some embodiments include a dosage form comprising: 1) an inclusioncomplex of meloxicam and a cyclodextrin, or 2) meloxicam and a carbonateor a bicarbonate.

Some embodiments include a method of administering meloxicam orally,comprising orally administering a dosage form described herein to apatient in need of treatment.

Some embodiments include a method of administering meloxicamintravenously, comprising intravenously administering a dosage formdescribed herein to a patient in need of treatment.

Disclosed herein are formulations for an inclusion complex ofcyclodextrin and meloxicam with bicarbonate and methods of use thereof.

Disclosed herein are formulations and methods for delivering meloxicamwith cyclodextrin to a subject by oral, enteral, intravenous,intramuscular, subcutaneous, intranasal, or other parenteral means.

Disclosed also are methods for treating pain and pain associated withconditions by delivering a dosage form with meloxicam, cyclodextrin, andbicarbonate by oral, enteral, intravenous, intramuscular, subcutaneous,intranasal, or other parenteral means to a subject.

A combination of rizatriptan and meloxicam (referred to herein forconvenience as a “subject combination”) may be used to treat a varietyof pain conditions.

Rizatriptan has the structure as shown below.

Some embodiments include a subject combination comprising: 1) aninclusion complex of meloxicam and a cyclodextrin, 2) rizatriptan, and3) a bicarbonate for treating migraine in a human being. The migrainemay be treatment-resistant migraine. The human being may have a historyof inadequate response to prior treatments.

Some embodiments include a subject combination comprising rizatriptanand meloxicam that has rapid, sustained, substantial and statisticallysignificant efficacy as compared to placebo, rizatriptan, or meloxicamin the acute treatment of migraine in patients with a history ofinadequate response to prior acute treatments.

Some embodiments include a subject combination comprising rizatriptanand meloxicam that requires significantly less use of rescue medicationas compared to rizatriptan, meloxicam, or placebo.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a depiction of the results described in Example 2 andcontained in Table 6.

FIG. 2 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 3 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 4 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 5 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 6 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 7 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 8 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 9 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 10 is another depiction of the results described in Example 2 andcontained in Table 6.

FIG. 11 is a plot of meloxicam plasma concentration at various timepoints over the first 24 hours for an embodiment of a dosage formdescribed herein and a commercially available meloxicam dosage form.

FIG. 12 is a plot of meloxicam plasma concentration at various timepoints over the first 24 hours for a dosage form ofMeloxicam/Rizatriptan described in Example 6 and a commerciallyavailable meloxicam dosage form.

FIG. 13 is a plot of rizatriptan plasma concentration at various timepoints over the first 12 hours for a dosage form ofMeloxicam/Rizatriptan described in Example 6 and a commerciallyavailable meloxicam dosage form.

FIG. 14 shows plots of the percentages of subjects reporting pain reliefat various time points over the first 4 hours post dose of the dosageforms of Meloxicam/Rizatriptan, rizatriptan, MoSEIC meloxicam, andplacebo described in Example 11.

FIG. 15 shows the percentages of subjects achieving pain freedom at 2hours, 4 hours, 12 hours, and 16 hours post dose of the dosage forms ofMeloxicam/Rizatriptan, rizatriptan, MoSEIC meloxicam, and placebodescribed in Example 11.

FIG. 16A shows the percentages of subjects achieving sustained painfreedom from 2 hours to 24 hours post dose of the dosage forms ofMeloxicam/Rizatriptan, rizatriptan, MoSEIC meloxicam, and placebodescribed in Example 11.

FIG. 16B shows the percentages of subjects achieving sustained painrelief from 2 hours to 24 hours post dose of the dosage forms ofMeloxicam/Rizatriptan, rizatriptan, MoSEIC meloxicam, and placebodescribed in Example 11.

FIG. 17A shows the percentages of subjects achieving sustained painfreedom from 2 hours to 48 hours post dose of the dosage forms ofMeloxicam/Rizatriptan, rizatriptan, MoSEIC meloxicam, and placebodescribed in Example 11.

FIG. 17B shows the percentages of subjects achieving sustained painrelief from 2 hours to 48 hours post dose of the dosage forms ofMeloxicam/Rizatriptan, rizatriptan, MoSEIC meloxicam, and placebodescribed in Example 11.

FIG. 18 shows the percentages of subjects who took rescue medicationthrough hour 24 post dose of the dosage forms of Meloxicam/Rizatriptan,rizatriptan, MoSEIC meloxicam, and placebo described in Example 11.

DETAILED DESCRIPTION

Provided herein are dosage forms with NSAIDs (such as meloxicam) andcyclodextrin (optionally in an inclusion complex), and/or bicarbonate,and methods of treatment using the dosage form.

A dosage form may be given enterally including, but not limited to,oral, sublingual, or rectal delivery, or parenterally including, but notlimited to, intravenous, intramuscular, intranasal, or subcutaneousdelivery.

Some methods include administration of a product that combines an NSAIDthat is formulated with: a) a cyclodextrin and/or b) a buffering agent.In some embodiments, the method involves treating a patient with apharmaceutical formulation comprising meloxicam and a cyclodextrinand/or a carbonate/bicarbonate. Method embodiments may also includetreating a patient to increase the bioavailability of meloxicam in thepatient or increase the rate at which the meloxicam becomesbioavailable.

The combination of meloxicam, a cyclodextrin (such as SBEβCD), and abicarbonate (such as sodium bicarbonate) may substantially increase thesolubility and rate of absorption of meloxicam after oraladministration, while maintaining its extended plasma concentrationhalf-life in mammals, such as humans after oral administration.

The combination of meloxicam, a cyclodextrin (such as SBEβCD), and abicarbonate (such as sodium bicarbonate) may substantially increase theoral bioavailability of meloxicam in mammals, such as humans, after oraladministration.

Unless otherwise indicated, any reference to a compound herein, such asmeloxicam or rizatriptan, by structure, name, or any other means,includes pharmaceutically acceptable salts, alternate solid forms, suchas polymorphs, solvates, hydrates, enantiomers, tautomers,deuterium-modified forms, or any other chemical species, such asprecursors, prodrugs, or any other chemical species that may rapidlyconvert to a compound described herein under conditions in which thecompounds are used as described herein.

A subject combination may be given enterally including, but not limitedto, oral, sublingual, or rectal delivery, or parenterally including, butnot limited to, intravenous, intramuscular, intranasal, or subcutaneousdelivery. In some embodiments, both meloxicam and rizatriptan areadministered orally. In some embodiments, meloxicam is administeredintravenously and rizatriptan is administered orally. In someembodiments, meloxicam is administered intramuscularly and rizatriptanis administered orally.

Normally, the combination of meloxicam and rizatriptan is administeredso that the human being receives the meloxicam and rizatriptan within ashort period of time with respect to one another. For example, themeloxicam and rizatriptan may be administered within about 2 hours,within about 1 hour, within about 30 minutes, within about 20 minutes,within about 15 minutes, within about 10 minutes, within about 5minutes, or within about 1 minute of one another. In some embodiments,the meloxicam and rizatriptan are administered simultaneously, which forthe purpose of this disclosure includes administration within about 5minutes. In some embodiments, the meloxicam and rizatriptan areadministered in a single dosage form.

The term “treating” or “treatment” broadly includes any kind oftreatment activity, including the diagnosis, cure, mitigation, orprevention of disease in man or other animals, or any activity thatotherwise affects the structure or any function of the body of man orother animals.

The dosage form or the subject combination may be used to treat, orprovide relief of, any type of pain including, but not limited to,migraine and other types of headache, inflammatory pain, musculoskeletalpain, neuropathic pain, chronic pain, acute pain, localized pain,systemic pain, cancer-related pain, acute pain, pain due to injury, paindue to illness (e.g., fever), post-operative pain, etc. In someinstances, pain relief may be palliative, or pain relief may be providedindependent of improvement of the disease or condition or the underlyingcause of the disease or condition. For example, although the underlyingdisease may not improve, or may continue to progress, an individualsuffering from the disease may experience pain relief. In someembodiments, the pain affects a muscle, nerve, cartilage, bone,ligament, tendon, tendon sheaths, bursae, or joint.

Migraine is a disabling neurological disorder characterized by recurrentattacks of pulsating head pain accompanied by nausea and sensitivity tolight and sound. This pain may be moderate to severe, but is oftensevere and incapacitating, requiring bed rest. The headaches may affectone half of the head, may be pulsating in nature, and may last from 2 to72 hours. Associated symptoms may include nausea, vomiting, andsensitivity to light (photophobia), sound (phonophobia), or smell. Themigraine pain may be accompanied by disturbed vision. The migraine paincan be made worse by physical activity. Migraines may be associated withan aura, which may be a short period of visual disturbance which signalsthat the headache will soon occur. Some migraine patients may not haveaura.

In some embodiments, the human being who is being treated for migrainepain suffers from allodynia, such as cutaneous allodynia with theirmigraine attacks. Allodynia, such as cutaneous allodynia, which is painfrom normally non-painful stimuli (such as brushing hair, wearingglasses, taking a shower, etc.). Patients having allodynia, such ascutaneous allodynia are believed to be less likely to respond well totriptan medications.

Current treatments are suboptimal, with more than 70% of sufferersreporting dissatisfaction with existing acute treatments. The mostcommonly reported reasons for patient dissatisfaction are slow onset ofpain relief, inconsistent pain relief, and recurrence of pain during thesame day. Suboptimal acute treatment is associated with a significantlyincreased risk of new-onset chronic migraine, which may be prevented byimproving acute treatment outcomes.

Administering a subject combination to a human being suffering frommigraine, such as an acute attack of migraine pain or aura, may quicklyresult in a reduction in a migraine symptom, such as pain, nausea,vomiting, photophobia, or phonophobia, such as at or within about 5minutes (intended as a shorthand for “at about 5 minutes, or withinabout 5 minutes”), at or within about 10 minutes, at or within about 30minutes, at or within about 1 hour, at or within about 90 minutes, at orwithin about 2 hours, at or within about 2.5 hours, or at or withinabout 3 hours. In some embodiments, a human being experiences areduction of, or complete relief from, pain, such as headache pain ormigraine pain, nausea, vomiting, photophobia, and/or phonophobia, at orwithin about 1 hour, at or within about 90 minutes, at or within about 2hours, at or within about 2.5 hours, or at or within about 3 hours. Insome embodiments, the relief experienced, is greater than would beexperienced by receiving the same amount of rizatriptan withoutmeloxicam. In some embodiments, the relief experienced, is greater thanwould be experienced by receiving the same amount of meloxicam withoutrizatriptan.

The combination of meloxicam and rizatriptan may have distinct dualmechanisms of action for the acute treatment of migraine. Meloxicam is apotent, COX-2 preferential NSAID which is limited by slow absorption.Rizatriptan is a potent 5-HT1_(B/D) agonist believed to have efficacy inmigraine.

Observation of relief or reduction in a symptom at a specific period oftime, such as “at 2 hours,” is useful because it allows theeffectiveness of the treatment to be evaluated at a specific orconsistent time point, which facilitates comparison between patients.Observation of relief or reduction in a symptom within a specific periodof time, such as “within about 2 hours,” is useful because it isdesirable for relief or reduction of a symptom to occur as early aspossible, and specifying that relief occur within a specified time setsa guideline in which it is desirable that relief occur.

For some methods, administration of the subject combination may achievea reduction in migraine pain, nausea, vomiting, photophobia, orphonophobia that lasts at least about one hour, at least about twohours, at least about three hours, at least about four hours, at leastabout six hours, at least about eight hours, about 8-24 hours, about 24hours, or more than 24 hours.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater pain relief than thehuman being would have experienced two hours after receiving the sameamount of meloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater painrelief than the human being would have experienced twenty-four hoursafter receiving the same amount of meloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater pain relief than thehuman being would have experienced two hours after receiving the sameamount of rizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater painrelief than the human being would have experienced twenty-four hoursafter receiving the same amount of rizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater relief from nauseathan the human being would have experienced two hours after receivingthe same amount of meloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom nausea than the human being would have experienced twenty-fourhours after receiving the same amount of meloxicam without therizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater relief from nauseathan the human being would have experienced two hours after receivingthe same amount of rizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom nausea than the human being would have experienced twenty-fourhours after receiving the same amount of rizatriptan without themeloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater relief from vomitingthan the human being would have experienced two hours after receivingthe same amount of meloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom vomiting than the human being would have experienced twenty-fourhours after receiving the same amount of meloxicam without therizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater relief from vomitingthan the human being would have experienced two hours after receivingthe same amount of rizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom vomiting than the human being would have experienced twenty-fourhours after receiving the same amount of rizatriptan without themeloxicam. In some embodiments, the meloxicam and the rizatriptan areadministered simultaneously (e.g. in a single dosage form, such as asingle oral dosage form), and two hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom photophobia than the human being would have experienced two hoursafter receiving the same amount of meloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom photophobia than the human being would have experienced twenty-fourhours after receiving the same amount of meloxicam without therizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater relief fromphotophobia than the human being would have experienced two hours afterreceiving the same amount of rizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom photophobia than the human being would have experienced twenty-fourhours after receiving the same amount of rizatriptan without themeloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater relief fromphonophobia than the human being would have experienced two hours afterreceiving the same amount of meloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom phonophobia than the human being would have experienced twenty-fourhours after receiving the same amount of meloxicam without therizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater relief fromphonophobia than the human being would have experienced two hours afterreceiving the same amount of rizatriptan without the meloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom phonophobia than the human being would have experienced twenty-fourhours after receiving the same amount of rizatriptan without themeloxicam.

In some embodiments, the human being receiving the subject combinationhas a history of inadequate response to prior migraine treatments. Forexample, if the human being is asked whether he or she was pain-freewithin two hours of treatment for most attacks, and given the option ofanswering “never,” “rarely,” “less than half the time,” or “half thetime or more;” and the human being answers “never,” “rarely,” or “lessthan half the time,” then the human being has had an inadequate responseto the treatment. Similarly, if the human being is asked whether onedose of medication usually relieved the human being's headache and keptit away for at least 24 hours, and given the option of answering“never,” “rarely,” “less than half the time,” or “half the time ormore;” and the human being answers “never,” “rarely,” or “less than halfthe time,” then the human being has had an inadequate response to thetreatment.

In some embodiments, the human being receiving the subject combinationhas indicated that he or she was “never” pain-free within two hours oftreatment for most attacks. In some embodiments, the human beingreceiving the subject combination has indicated that he or she was“rarely” pain-free within two hours of treatment for most attacks. Insome embodiments, the human being receiving the subject combination hasindicated that he or she was pain-free within two hours of treatment formost attacks “less than half the time.”

In some embodiments, the human being receiving the subject combinationhas indicated that one dose of medication “never” relieved therespondent's headache and kept it away for at least 24 hours. In someembodiments, the human being receiving the subject combination hasindicated that one dose of medication “rarely” relieved the respondent'sheadache and kept it away for at least 24 hours. In some embodiments,the human being receiving the subject combination has indicated that onedose of medication relieved the respondent's headache and kept it awayfor at least 24 hours “less than half the time.”

In some embodiments, the human being receiving the subject combinationhas a history of inadequate response to prior migraine treatments asassessed by a total mean score of less than 7, less than 6, less than 5,less than 4, less than 3, less than 2, 1-2, 2-3, 3-4, 4-5, 5-6, or 6-7on the Migraine Treatment Optimization Questionnaire (mTOQ-4). In someembodiments, the human being has had prior triptan use before receivesthe subject combination, such as a combination comprising meloxicam andrizatriptan.

In some embodiments, the human being receiving the subject combination,such as a combination comprising meloxicam and rizatriptan, hasmigraine, and may have a history of inadequate response to priormigraine treatments. In some embodiments, the human being havingmigraine does not have cluster headaches or other types of migraines. Insome embodiments, the human being having migraine does not have chronicdaily headache. In some embodiments, the human being having migrainedoes not have more than 15, 15-20, 20-25, 25-28, 28-30, or 30-31non-migraine headache days per month. In some embodiments, the humanbeing having migraine does not have a history of significantcardiovascular disease. In some embodiments, the human being havingmigraine does not have uncontrolled hypertension.

In some embodiments, the dosage form may also be administered to relievearthritis pain. In some embodiments the dosage form may be administeredto relieve other signs and/or symptoms of arthritis. Examples ofarthritis include, but are not limited to, rheumatoid arthritis,juvenile rheumatoid arthritis (pauciarticular and polyarticular course),osteoarthritis, erosive osteoarthritis, sero-negative (non-rheumatoid),arthropathies, non-articular rheumatism, peri-articular disorders, axialspondyloarthritis, transient osteoarthritis of the hip, vertebral crushfractures, osteoporosis, and neuropathic arthropathies includingCharcot's foot, axial spondyloarthritis including ankylosingspondylitis, and SAPHO syndrome. In other embodiments, the arthritispain may be chronic or acute. In some embodiments the dosage form may beadministered to relief the signs and/or symptoms of an arthritisincluding but not limited osteoarthritis

For some methods, administration of the dosage form may achieve areduction in pain that lasts at least about one hour, two hours, threehours, four hours, six hours, at least about eight hours, about eight toabout 24 hours, or about 24 hours. In other embodiments, administrationof the dosage form may achieve a reduction in pain that is observed atabout 10 minutes, at about 30 minutes, at about one hour, at about twohours, at about three hours, at about four hours, at about five hours,at about six hours, at less than 15 minutes, at less than 20 minutes, 30minutes, at less than one hour, at less than two hours, at less thanthree hours, at about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 60minutes, or other time period bound by these ranges, afteradministration of the dosage form.

In some embodiments, the dosage form may also be administered to relieveneuropathic pain, including diabetic peripheral neuropathy,post-herpetic neuralgia, trigeminal neuralgia, monoradiculopathies,phantom limb pain, sciatica, pudendal neuralgia, and central pain. Othercauses of neuropathic pain may include, but are not limited to,cancer-related pain, lumbar nerve root compression, spinal cord injury,post-stroke pain, central multiple sclerosis pain, HIV-associatedneuropathy, and radio-therapy or chemo-therapy associated neuropathy.The neuropathic pain treated may be chronic or acute.

In some methods, the dosage form may be administered to relieveinflammatory pain including inflammatory musculoskeletal pain, pain dueto injury, arthritis pain, and complex regional pain syndrome. In otherembodiments, the inflammatory pain may be chronic or acute.

Arthritis refers to inflammatory joint diseases that can be associatedwith pain. Examples of arthritis pain include but are not limited topain associated with osteoarthritis, erosive osteoarthritis, rheumatoidarthritis, juvenile rheumatoid arthritis, sero-negative (non-rheumatoid)arthropathies, non-articular rheumatism, peri-articular disorders,neuropathic arthropathies including Charcot's foot, axialspondyloarthritis including ankylosing spondylitis, and SAPHO syndrome.The inflammatory joint disease treated may be chronic or acute.

For some methods, the meloxicam may be administered to relievemusculoskeletal pain. Examples of musculoskeletal pain may include, butare not limited to, back pain, low back pain (e.g., lumbosacral pain),neck pain, infection, cramps, tendonitis, epidondylitis, carpal tunnelsyndrome, joint pain, fibromyalgia, pain due to injury, Tunnelsyndromes, pain associated with bone fractures, sprains, fibrousdysplasia, osteogenesis imperfecta, Paget's disease of bone, transientosteoporosis, and transient osteoporosis of the hip. In otherembodiments, the musculoskeletal pain may be chronic or acute.

For some methods, administration of the dosage form or the subjectcombination may achieve a reduction in pain that lasts at least aboutone hour, at least about two hours, at least about three hours, at leastabout four hours, at least about six hours, at least about eight hours,about 8 to about 24 hours, or about 24 hours. In other embodiments,administration of the subject combination may achieve a reduction inpain that is observed at about 10 minutes, at about 30 minutes, at aboutone hour, at about two hours, at about three hours, at about four hours,at about five hours, at about six hours, at or within about 5 minutes,at or within about 10 minutes, at or within about 15 minutes, at orwithin about 20 minutes, at or within about 25 minutes, at or withinabout 30 minutes, at or within about 35 minutes, at or within about 40minutes, at or within about 45 minutes, at or within about 50 minutes,or at or within about 60 minutes, at two hours or less, at three hoursor less, or other time period bound by these ranges, afteradministration of the subject combination.

A human being that is treated for a disease or condition with the dosageforms described herein may be of any age. For example the person mayhave an age of about 10 years to about 90 years, about 20 years to about80 years, about 30 years to about 75 years, about 40 years to about 70years, about 1 year to about 16 years, about 80 years to about 95 years,about 18 years or more, about 20 years or more, about 25 years or more,about 30 years or more, about 40 years or more, about 45 years or more,about 50 years or more, about 55 years or more, about 60 years or more,about 65 years or more, or any other age in a range bounded by, orbetween, these values.

In some embodiments, a human being who is treated for migraine with thedosage forms described herein, for example comprising meloxicam,rizatriptan, SBEβCD, and a bicarbonate such as sodium bicarbonate, maybe of 18 years to 65 years of age, about 18-20 years of age, about 20-25years of age, about 25-30 years of age, about 30-40 years of age, about40-45 years of age, about 40-50 years of age, about 50-60 years of age,about 60-65 years of age, or any other age in a range bounded by, orbetween, these values.

In some embodiments, a human being who is treated for migraine with adosage forms described herein, such as a dosage form comprisingmeloxicam, rizatriptan, SBEβCD, and a bicarbonate such as sodiumbicarbonate, may be white, black or African American, or Asian.

In some embodiments, a human being that is treated for a disease orcondition with a dosage form comprising meloxicam or another NSAID hassuffered from the pain or condition associated with the pain for atleast 1 day, at least one week, at least 2 weeks, at least 1 month, atleast 6 weeks, at least 2 months, at least 3 months, at least 6 months,or at least 1 year, or any duration in a range bounded by, or between,these values.

In some embodiments, a human being that is treated for migraine with adosage form comprising meloxicam and rizatriptan has been diagnosed ofmigraine with or without aura as defined by the ICHD-3 criteria for atleast 3 months, at least 6 months, at least 1 year, at least 2 years,about 1-2 years, 2-3 years, or longer, or at least 1 year, or anyduration in a range bounded by, or between, these values.

In some embodiments, a human being has an average 2 to 8, 2-3, 3-4, 4-5,5-6, 6-7, or 7-8 moderate to severe migraines per month.

A cyclodextrin used in a dosage form with meloxicam could include acyclodextrin, a cyclodextrin derivative, and/or a salt thereof. Aninclusion complex of meloxicam and cyclodextrin may be morewater-soluble relative to the non-complexed meloxicam. The cyclodextrinmay be a naturally-occurring cyclodextrin (e.g., α, β, orγ-cyclodextrins) or a synthetic cyclodextrin. In some embodiments,α-cyclodextrins, derivatives, or salts thereof may be used.α-Cyclodextrins may include, but are not limited to,(2,3,6-tri-O-acetyl)-α-cyclodextrin,(2,3,6-tri-O-methyl)-α-cyclodextrin, (2,3,6-tri-O-octyl)-α-cyclodextrin,6-bromo-6-deoxy-α-cyclodextrin, 6-iodo-6-deoxy-α-cyclodextrin,(6-O-tertbutyl-dimethylsilyl)-α-cyclodextrin, butyl-α-cyclodextrin,succinyl-α-cyclodextrin, (2-hydroxypropyl)-α-cyclodextrin, orcombinations thereof.

In some embodiments, β-cyclodextrins, derivatives, or salts thereof maybe used. β-cyclodextrins may include, but are not limited to,hydroxypropyl-β-cyclodextrin, 6-monodeoxy-6-monoamino-β-cyclodextrin,glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin,6-O-α-D-glucosyl-β-cyclodextrin, 6-O-α-maltosyl-β-cyclodextrin,6-azido-6-deoxy-β-cyclodextrin,(2,3-di-O-acetyl-6-O-sulfo)-β-cyclodextrin, methyl-β-cyclodextrin,dimethyl-β-cyclodextrin (DMβCD), trimethyl-β-cyclodextrin (TMβCD),(2,3-di-O-methyl-6-O-sulfo)-β-cyclodextrin,(2,6-di-O-methyl)-β-cyclodextrin, (2,6-di-O-ethyl)-β-cyclodextrin,(2,3,6-tri-O-methyl)-β-cyclodextrin,(2,3,6-tri-O-acetyl)-β-cyclodextrin,-(2,3,6-tri-O-benzoyl)-β-cyclodextrin,(2,3,6-tri-O-ethyl)-β-cyclodextrin, 6-iodo-6-deoxy-β-cyclodextrin,6-(dimethyl-tert-butylsilyl)-6-deoxy-β-cyclodextrin,6-bromo-6-deoxy-β-cyclodextrin, monoacetyl-(3-cyclodextrin,diacetyl-β-cyclodextrin, triacetyl-β-cyclodextrin,(3-O-acetyl-2,6-di-O-methyl)-β-cyclodextrin,(6-O-maltosyl)-β-cyclodextrin, (6-O-sulfo)-β-cyclodextrin,(6-O-t-butyldimethylsilyl-2,3-di-O-acetyl)-β-cyclodextrin,succinyl-(2-hydroxypropyl)-β-cyclodextrin,(2,6-di-O-)ethyl-β-cyclodextrin, (2-carboxyethyl)-β-cyclodextrin(CMEβCD), hydroxyethyl-β-cyclodextrin (HEβCD),(2-hydroxypropyl)-β-cyclodextrin, (2-hydroxypropyl)-β-cyclodextrin(HPβCD), (3-hydroxypropyl)-β-cyclodextrin (3HPβCD),(2,3-hydroxypropyl)-β-cyclodextrin (DHPβCD), butyl-β-cyclodextrin,methyl-β-cyclodextrin,silyl((6-O-tert-butyldimethyl)-2,3,-di-O-acetyl)-β-cyclodextrin,succinyl-β-cyclodextrin, (2-hydroxyisobutyl)-β-cyclodextrin, randomlymethylated-β-cyclodextrin, branched-β-cyclodextrin, or combinationsthereof.

In other embodiments, a β-cyclodextrin may be a sulfoalkyl ethercyclodextrin, derivative, or salt thereof. Examples of sulfoalkyl ethercyclodextrin derivatives may include, but are not limited to, sulfobutylether-β-cyclodextrin (e.g., SBEβCD, betadex, CAPTISOL®). In someembodiments, a SBEβCD may have about 4-8, about 5-8, about 4-7, about6-7, or about 6.5 sulfobutyl ether groups per cyclodextrin molecule.

In some embodiments, γ-cyclodextrins, derivatives, or salts thereof maybe used. γ-cyclodextrins may include carboxymethyl-γ-cyclodextrin,(2,3,6-tri-O-acetyl)-γ-cyclodextrin,(2,3,6-tri-O-methyl)-γ-cyclodextrin, (2,6-di-O-pentyl)-γ-cyclodextrin,6-(dimethyl-tert-butylsilyl)-6-deoxy-γ-cyclodextrin,6-bromo-6-deoxy-γ-cyclodextrin, 6-iodo-6-deoxy-γ-cyclodextrin,(6-O-t-butyldimethylsilyl)-γ-cyclodextrin, succinyl-γ-cyclodextrin,hydroxypropyl-γ-cyclodextrin (2-hydroxypropyl)-γ-cyclodextrin,acetyl-γ-cyclodextrin, butyl-γ-cyclodextrin, or combinations thereof.

In some embodiments, the dosage form may include a bicarbonate, such assodium bicarbonate, potassium bicarbonate, magnesium bicarbonate,calcium bicarbonate, ammonium bicarbonate, or a combination thereof. Abicarbonate may help to increase bioavailability of the meloxicam.

In other embodiments, the dosage form may include a carbonate,derivatives, or salts thereof. Examples of carbonates may includealuminum carbonate, ammonium carbonate, barium carbonate, calciumcarbonate, cobalt(II) carbonate, lanthanum carbonate, lithium carbonate,magnesium carbonate, manganese(II) carbonate, potassium carbonate,sodium carbonate, or combinations thereof.

In some embodiments, enhanced bioavailability of the dosage form may beachieved in treating one of these conditions by administering a dosageform comprising a salt form of the meloxicam, by creating an inclusioncomplex with meloxicam and cyclodextrin, and/or by including abicarbonate. This may allow a reduced molar amount of the meloxicam tobe used as compared to other meloxicam dosage forms.

Unless otherwise indicated, any reference to a compound herein, such asmeloxicam or a cyclodextrin, by structure, name, or any other means,includes pharmaceutically acceptable salts, alternate solid forms, suchas polymorphs, solvates, hydrates, enantiomers, tautomers,deuterium-modified forms, or any other chemical species that may rapidlyconvert to a compound described herein under conditions in which thecompounds are used as described herein.

In some embodiments, use of a cyclodextrin, a carbonate, or abicarbonate may improve the oral bioavailability of meloxicam by atleast about 10%, at least about 20%, at least about 30%, at least about40%, at least about 50%, at least about 60%, at least about 70%, atleast about 80%, at least about 90%, up to about 100%, up to about 200%,or any amount in a range bounded by, or between, these values ascompared to administration of meloxicam alone.

Due to the improved bioavailability, the dosage form may contain, or asubject may receive, on a molar basis, less of the meloxicam than wouldotherwise be administered. For example, a dosage form may contain, or amammal may receive, at least about 10 mole % less, at least about 20mole % less, at least about 30 mole % less, at least about 40 mole %less, at least about 50 mole % less, at least about 60 mole % less, atleast about 70 mole % less, at least about 80 mole % less, at leastabout 85 mole % less, and/or up to about 90 mole % less, 95 mole % less,or any amount in a range bounded by, or between, these values as wouldotherwise be administered of meloxicam.

In other embodiments, use of other NSAIDs, opioids, or other painmedications may be reduced by at least about 5%, at least about 10%, atleast about 15%, at least about 20%, at least about 25%, at least about30%, at least about 35%, at least about 40%, at least about 45%, atleast about 50%, at least about 60%, at least about 70%, at least about80%, or at least about 90%, up to about 100%, as compared to the use ofother NSAIDs, opioids or other pain medications without administrationof meloxicam with cyclodextrin, carbonate, and/or bicarbonate.

In some embodiments, a dosage form may contain meloxicam in an amountfrom about 1-50 mg; about 1-10 mg; about 1-5 mg; about 10-40 mg; about1-35 mg; about 1-25 mg; about 1-15 mg; about 5-20 mg; about 5-10 mg;about 5-15 mg; about 10-20 mg; about 20-30 mg; about 30-40 mg; about40-50 mg; about 5 mg; about 7.5 mg; about 10 mg; about 15 mg; about 30mg; or any amount in a range bounded by, or between, any of thesevalues. These doses may be a safe dose for repeated administration, suchas once hourly dosing to once daily dosing, twice daily dosing, dosingone to 12 times daily, doing 3, 4, 5, or 6 times daily, etc. In someembodiments, the meloxicam may be safely administered 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 times, or about 3 to about 10 times aday, once a day, or less frequently, such as once a week, once every twoweeks, once a month, etc.

For some dosage forms, meloxicam forms a complex with thesubstituted-β-cyclodextrin or other another cyclodextrin which may beformulated into a solid dosage form. Such a dosage form may be suitablefor oral administration. A meloxicam-cyclodextrin inclusion complex mayalso be dissolved in water or another solvent to form a parenteralformulation. However, physical mixtures of meloxicam and thesubstituted-β-cyclodextrin or other cyclodextrins may also be used inoral or parenteral dosage forms.

Formation of an inclusion complex of meloxicam and a cyclodextrin mayhelp to improve the properties of a dosage form. For some inclusioncomplexes, the meloxicam and the cyclodextrin (e.g., SBEβCD) may have amolar ratio of about 0.5-2 (a molar ratio of 0.5 is 0.5 moles ofmeloxicam to 1 mole of cyclodextrin), about 0.5-0.7, about 0.6-0.8,about 0.7-0.9, about 0.8-1, about 0.9-1.1, about 1-1.2, about 1.1-1.3,about 1.2-1.4, about 1.3-1.5, about 1.4-1.6, about 1.5-1.7, about1.6-1.8, about 1.7-1.9, about 1.8-2, about 0.8-1.2, about 1, or anyratio in a range bounded by any of these values.

For some dosage forms, a cyclodextrin (e.g., SBEβCD) may be employed ina weight ratio to the meloxicam within the range from about 1-1000 (e.g.1 g of cyclodextrin per 1 g of meloxicam is a weight ratio of 1); about1-20; about 1-10; about 1-15; about 2-4, about 3-5, about 4-6, about5-7, about 6-8, about 7-9, about 8-10, or any weight ratio in a rangebounded by, or between, any of these values. For some dosage forms, acyclodextrin (e.g., SBEβCD) may be employed in a weight ratio to themeloxicam within the range from about 0.001-1 (e.g. 0.1 g ofcyclodextrin per 1 g of meloxicam is a weight ratio of 0.1); about0.01-1; about 0.05-1; about 0.1-1; about 0.2-1; about 0.3-1, about0.4-1, about 0.5-1, about 0.6-1, about 0.7-1, about 0.8-1, or any weightratio in a range bounded by, or between, any of these values. Each typeof cyclodextrin employed may have a different ratio.

For some dosage forms, the cyclodextrin may be present in an amount fromabout 1-200 mg; 25-175 mg; about 50-150 mg; about 25-100 mg; about75-150 mg; about 100-175 mg; about 20-80 mg; about 25-50 mg; about60-100 mg; about 80-100 mg; about 80-120 mg; about 100-120 mg; about100-140 mg; about 120-160 mg; about 140-180 mg; about 30-90 mg; about40-80 mg; about 50-70 mg, about 55-65 mg, about 60-62 mg, or any amountin a range bounded by, or between, any of these values.

For some methods, the inclusion complex of meloxicam and cyclodextrinsuch as a substituted-β-cyclodextrin is delivered orally (for example bytablet, capsule, elixir, or the like). Other potential routes ofadministration include intravenous, intramuscular, intranasal,lyophilized parenteral, subcutaneous, transdermal, transmucosal, orthrough other parenteral means. The meloxicam may also be deliveredalone or non-complexed with cyclodextrin.

Some dosage forms contain a bicarbonate (e.g., sodium bicarbonate) inamount from about 1-2000 mg; about 1-1000 mg; about 100-1000 mg; about200-800 mg; about 1-500 mg; about 1-200 mg; about 1-100 mg; about 50-750mg; about 500-1000 mg; about 100-500 mg; about 100-300 mg; about500-1000 mg; about 300-700 mg; about 400-600 mg; about 50-250 mg; about250-750 mg; about 100-200 mg; about 200-300 mg; about 300-400 mg; about400-500 mg; about 410-510 mg; about 420-520 mg; about 430-530 mg; about440-540 mg; about 450-550 mg; about 460-560 mg; about 470-570 mg; about480-580 mg; about 490-590 mg; about 500-600 mg; about 600-700 mg; about700-800 mg; about 800-900 mg; about 150-650 mg; about 350-850 mg; or anyamount in a range bounded by, or between, any of these values.

Some dosage forms contain a carbonate in amount from about 1-1000 mg;about 1-500 mg; about 1-200 mg; about 1-100 mg; about 50-750 mg; about500-1000 mg; about 100-500 mg; about 100-300 mg; about 200-800 mg; about500-1000 mg; about 300-700 mg; about 400-600 mg; about 50-250 mg; about250-750 mg; about 100-200 mg; about 200-300 mg; about 300-400 mg; about400-500 mg; about 500-600 mg; about 600-700 mg; about 700-800 mg; about800-900 mg; about 150-650 mg; about 350-850 mg; or any amount in a rangebounded by, or between, any of these values.

In some embodiments, the daily dose of meloxicam (e.g., an oral dose, aparenteral dose, etc.) is about 2-5 mg, about 2-6 mg, about 2-7 mg,about 2-8 mg, about 2-9 mg, about 2-10 mg, about 2-11 mg, about 2-12 mg,about 2-13 mg, about 2-14 mg, about 2-15 mg, about 2-16 mg, about 2-17mg, about 2-18 mg, about 2-19 mg, about 2-20 mg, about 2-21 mg, about2-22 mg, about 2-23 mg, about 2-24 mg, about 2-25 mg, about 2-26 mg,about 2-27 mg, about 2-28 mg, about 2-29 mg, about 2-30 mg, about 2-35mg, about 2-40 mg, about 5-10 mg, about 10-15 mg, about 15-20 mg, about20-25 mg, about 25-30 mg, about 30-35 mg, or any amount in a rangebounded by any of these values.

In some embodiments, the weekly dose of meloxicam (e.g., an oral dose)is about 1-1000 mg; about 1-500 mg; about 10-250 mg; about 100-300 mg;about 10-100 mg; about 10-150 mg; about 10-300 mg; about 20-150 mg;about 20-60 mg; about 30-70 mg; about 40-60 mg; about 50-70 mg; about70-90 mg; about 90-110 mg; about 50 mg; about 55 mg; about 100-150 mg;about 30-100 mg; or any amount in a range bounded by, or between, any ofthese values. The weekly dose may be given as a single dose, given onceduring the week, or may be given in 2, 3, 4, 5, 6, or 7 individual dosesduring the week.

In some embodiments, the monthly dose of meloxicam (e.g., an oral dose),or a dose administered over a period of a month, is about 5000 mg orless; about 4000 mg or less; about 3000 mg or less; about 2000 mg orless; about 1000 mg or less; about 700 mg or less; about 600 mg or less;about 1-4000 mg; about 1-1000 mg; about 10-1000 mg; about 50-1000 mg;about 10-600 mg; about 40-600 mg; about 50-600 mg; about 40-400 mg;about 50-200 mg; about 200-240 mg; about 240-280 mg; about 280-320 mg;about 320-360 mg; about 360-400 mg; about 400-450 mg; about 450-500 mg;about 500-600 mg; about 250-350 mg; about 100-600 mg; about 40-2000 mg;about 40-800 mg; about 100-900 mg; about 100-800 mg; about 40-1000 mg;about 50-1000 mg; about 100-1000 mg; or any monthly dose in a rangebounded by, or between, any of these values. A monthly dose may be givenas a single dose, or as two or more individual doses administered duringthe month. In some embodiments, the monthly dose is administered in 2 or3 bi-weekly doses. In some embodiments, the monthly dose is administeredin 4 or 5 weekly doses. In some embodiments, the monthly dose isadministered in 28 to 31 daily doses, or in 56 to 62 daily doses ormore. In some embodiments, the monthly dose is administered in 5 to 15individual doses during the month. The monthly dose may be administeredfor only 1 month, or may be repeatedly administered for 2 or moremonths.

In other embodiments, the dosage form may be administered weekly forabout one, two, three, four, or more consecutive weeks, every other weekor bi-weekly, or once every three weeks. This regimen may be repeatedonce weekly, twice in a month, three times in a month, once monthly,once every two months, once every three months, or as directed by amedical professional.

In certain embodiments, the pharmaceutical composition results inincreased bioavailability (e.g., reduced T_(max), increased C_(max),increased AUC, etc.) of the meloxicam from the dosage form as comparedto a dosage form containing meloxicam but not containing a cyclodextrin,an acid inhibitor, or a buffering agent (such as a bicarbonate). In someembodiments, the bioavailability of meloxicam will increase withmultiple dosing. For example, the bioavailability of meloxicam in thedosage form may increase after about 1-10 days of dosing; about 2-6 daysof dosing; about 3-5 days of dosing; about 4-6 days of dosing; about 5-8days of dosing; about 5 days of dosing; about 6 days of dosing; about 7days of dosing; about 8 days of dosing; about 10 days of dosing; about15 days of dosing; or time in any range bounded by, or between, any ofthese values; as compared to the bioavailability of meloxicam in adosage form not containing a cyclodextrin, an acid inhibitor, or abuffering agent (such as a bicarbonate).

Some of the dosage forms may result in a desired range for an area underthe plasma concentration curve (AUC) of meloxicam. For example thedosage with meloxicam may result in an AUC of meloxicam of about 1-150μg·hr/mL; about 10-30 μg·hr/mL; about 20-40 μg·hr/mL; about 30-50μg·hr/mL; about 40-60 μg·hr/mL; about 50-70 μg·hr/mL; about 60-80μg·hr/mL; about 70-90 μg·hr/mL; about 80-100 μg·hr/mL; about 10-100μg·hr/mL; about 50-150 μg·hr/mL; about 25-125 μg·hr/mL; about 75-150μg·hr/mL; about 20-50 μg·hr/mL; about 40-70 μg·hr/mL; about 60-90μg·hr/mL; about 80-110 μg·hr/mL; about 100-130 μg·hr/mL; about 120-150μg·hr/mL; or any AUC in a range bounded by, or between, any of thesevalues.

Unless otherwise indicated, the AUC refers to the AUC calculated to thelast measured concentration (AUC_(0-t)), such as, over a period of 6hours (AUC₀₋₆), over a period of 12 hours (AUC₀₋₁₂), over a period of 24hours (AUC₀₋₂₄), or extrapolated to infinity (AUC_(0-inf)).

In Example 3 below, the AUC₀₋₂₄ of meloxicam in human beings for an oraldosage form containing sodium bicarbonate and sulfobutyletherβ-cyclodextrin (SBEβCD) was about 27 μg·hr/mL. This dosage formcontained 15 mg of meloxicam.

The 15 mg IV and intramuscular doses also provide an AUC₀₋₂₄ ofmeloxicam in human beings that is about 27 μg·hr/mL. The AUC ofmeloxicam is believed to be approximately dose proportional. So for thisoral dosage form, or for an IV or intramuscular dosage form, a meloxicamdose of, for example, approximately 17 mg to about 30 mg would beexpected to result in an AUC₀₋₂₄ of meloxicam of about 30-50 μg·hr/mL.

For some acute pain conditions, such as migraine and other types ofheadache, the AUC for a short period after oral administration, such asan AUC measured over 6 hours (or AUC₀₋₆), may be of particular interest.For example, some dosage forms may result in an AUC₀₋₆ of at least about6 μg·hr/mL; at least about 7 μg·hr/mL; at least about 8 μg·hr/mL; atleast about 9 μg·hr/mL; about 6-10 μg·hr/mL; about 7-11 μg·hr/mL; about8-12 μg·hr/mL; about 9-13 μg·hr/mL; or any AUC in a range bounded by, orbetween, any of these values.

In some embodiments, the dosage form may result in a C_(max) ofmeloxicam of about 10-2500 ng/mL; about 100-2250 ng/mL; about 500-2000ng/mL; about 1000-2500 ng/mL; about 1000-2000 ng/mL; about 100-900ng/mL; about 750-1500 ng/mL; about 1250-2000 ng/mL; about 1500-2300ng/mL; about 800-1200 ng/mL; about 1900-2400 ng/mL; about 50-500 ng/mL;about 400-950 ng/mL; about 900-1500 ng/mL; about 1100-2200 ng/mL; about1300-1600 ng/mL; about 1200-1500 ng/mL; about 1400-2100 ng/mL; about1500-1900 ng/mL; about 1600-2100 ng/mL; about 1700-2000 ng/mL; about1800-2000 ng/mL; about 1900-2500 ng/mL; about 150-1700 ng/mL; about1600-1800 ng/mL; about 1700-1900 ng/mL; about 1800-2000 ng/mL; about1900-2100 ng/mL; about 2000-2200 ng/mL; about 2100-2300 ng/mL; about2200-2400 ng/mL; about 2300-2500 ng/mL; about 2500-3000 ng/mL; or anyC_(max) in a range bounded by, or between, any of these values.

For example, a method described herein may reduce the T_(max) ofmeloxicam. In some embodiments, the method may include treating apatient to achieve the T_(max) of meloxicam in the patient within about10 minutes; about 20 minutes; about 30 minutes; about 40 minutes; about50 minutes; about 60 minutes; about 70 minutes; about 80 minutes; about90 minutes; about 100 minutes; about 110 minutes; about 120 minutes;about 180 minutes; about 1-10 hr; about 2-9 hr; about 3-7 hr; about 4-6hr; about 1-5 hr; about 2-7 hr; about 3-8 hr; about 4-9 hr; about 1-4hr; about 2-5 hr; about 3-6 hr; about 4-7 hr; about 5-8 hr; about 6-9hr; about 7-10 hr; after administration or any T_(max) in a rangebounded by, or between, any of these values.

In some embodiments, an oral dosage form may have a T_(max) of meloxicamthat is shorter than would be achieved by administering meloxicam byintramuscular injection. In some embodiments, an oral dosage form mayhave a T_(max) of meloxicam that is shorter, or may increase meloxicamplasma levels at a faster rate, by a factor of at least about 1.5, about2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about10, about 12, about 15, about 20, or by a factor of about 1.5-1000,about 2-100, about 3-100, about 4-100, about 5-100, about 6-100, about7-100, about 8-100, about 9-100, about 10-100, about 12-100, about15-100, about 20-100, or by a factor in a range bounded by any of thesevalues.

In some embodiments, a dosage form comprising meloxicam may result in aplasma concentration of meloxicam at 12 hours that is about 0.01-0.5μg/mL; about 0.5-0.7 μg/mL; about 0.6-0.8 μg/mL; about 0.7-0.9 μg/mL;about 0.8-1 μg/mL; about 0.9-1.1 μg/mL; about 1-1.2 μg/mL; about 1.1-1.3μg/mL; about 1.2-1.4 μg/mL; about 1.3-1.5 μg/mL; about 1.4-1.6 μg/mL;about 1.5-1.7 μg/mL; about 1.6-1.8 μg/mL; about 1.7-1.9 μg/mL; about1.8-2 μg/mL; about 1.9-2.1 μg/mL; about 2-2.2 μg/mL; about 2.1-2.3μg/mL; about 2.2-2.4 μg/mL; about 2.3-2.5 μg/mL; about 2.4-2.6 μg/mL;about 2.5-2.7 μg/mL; about 2.6-2.8 μg/mL; about 2.7-2.9 μg/mL; about2.8-3 μg/mL; about 2.9-3.1 μg/mL; about 3-3.2 μg/mL; about 3.1-3.3μg/mL; about 3.2-3.4 μg/mL; about 3.3-3.5 μg/mL; about 3.4-3.6 μg/mL;about 3.5-3.7 μg/mL; about 3.6-3.8 μg/mL; about 3.7-3.9 μg/mL; about3.8-4 μg/mL; or any plasma concentration in a range bounded by, orbetween, any of these values.

In some embodiments, meloxicam is administered at a dose that results ina meloxicam plasma level (such as a C_(avg), or average plasma level) ofabout 0.01-0.5 μg/mL; about 0.5-0.7 μg/mL; about 0.6-0.8 μg/mL; about0.7-0.9 μg/mL; about 0.8-1 μg/mL; about 0.9-1.1 μg/mL; about 1-1.2μg/mL; about 1.1-1.3 μg/mL; about 1.2-1.4 μg/mL; about 1.3-1.5 μg/mL;about 1.4-1.6 μg/mL; about 1.5-1.7 μg/mL; about 1.6-1.8 μg/mL; about1.7-1.9 μg/mL; about 1.8-2 μg/mL; about 1.9-2.1 μg/mL; about 2-2.2μg/mL; about 2.1-2.3 μg/mL; about 2.2-2.4 μg/mL; about 2.3-2.5 μg/mL;about 2.4-2.6 μg/mL; about 2.5-2.7 μg/mL; about 2.6-2.8 μg/mL; about2.7-2.9 μg/mL; about 2.8-3 μg/mL; about 2.9-3.1 μg/mL; about 3-3.2μg/mL; about 3.1-3.3 μg/mL; about 3.2-3.4 μg/mL; about 3.3-3.5 μg/mL;about 3.4-3.6 μg/mL; about 3.5-3.7 μg/mL; about 3.6-3.8 μg/mL; about3.7-3.9 μg/mL; about 3.8-4 μg/mL; about 0.1-20 μg/mL; about 0.5-15μg/mL; about 0.5-10 μg/mL; about 5-15 μg/mL; about 10-20 μg/mL; about7.5-15 μg/mL; about 2-10 μg/mL; about 1-8 μg/mL; about 1-6 μg/mL; about1-2 μg/mL; about 0.5-3.5 μg/mL; about 0.5-7 μg/mL; about 12-20 μg/mL;about 8-12 μg/mL; about 1-4 μg/mL; about 4-7 μg/mL; about 7-11 μg/mL;about 11-15 μg/mL; about 15-19 μg/mL; about 16-20 μg/mL; or any amountof meloxicam plasma level in a range bounded by, or between, any ofthese values.

Administration of a dosage form described herein may result in adecreased time to therapeutic plasma concentration of meloxicam. Thetherapeutic plasma concentration is the C_(avg) for a 15 mg dose ofMobic® meloxicam. In some embodiments, the time to therapeutic plasmaconcentration of meloxicam (T_(thera)) is about 10-30 minutes, about10-15 minutes, about 15-20 minutes, about 20-25 minutes, about 25-30minutes, about 10-20 minutes, about 20-30 minutes, about 16-18 minutes,or about 17 minutes.

A method described herein may reduce the T_(max) of rizatriptan. Forexample, the method may achieve a T_(max) of rizatriptan in the patientwithin about 50 minutes; within about 60 minutes; within about 70minutes; within about 80 minutes; or within about 90 minutes; at about40-60 minutes, at about 40-45 minutes, at about 45-50 minutes, at about50-55 minutes, or about 55-60 minutes after administration, or anyT_(max) in a range bounded by any of these values.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater relief from allodynia,such as cutaneous allodynia than the human being would have experiencedtwo hours after receiving the same amount of meloxicam without therizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom allodynia, such as cutaneous allodynia than the human being wouldhave experienced twenty-four hours after receiving the same amount ofmeloxicam without the rizatriptan.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and two hours after the meloxicam and the rizatriptan areadministered, the human being experiences greater relief from allodynia,such as cutaneous allodynia than the human being would have experiencedtwo hours after receiving the same amount of rizatriptan without themeloxicam.

In some embodiments, the meloxicam and the rizatriptan are administeredsimultaneously (e.g. in a single dosage form, such as a single oraldosage form), and twenty-four hours after the meloxicam and therizatriptan are administered, the human being experiences greater relieffrom allodynia, such as cutaneous allodynia than the human being wouldhave experienced twenty-four hours after receiving the same amount ofrizatriptan without the meloxicam.

One embodiment is a method for reducing the risk of gastrointestinalside effects in people taking NSAIDs for pain relief and for otherconditions, particularly during chronic treatment, and improving thebioavailability of the NSAID. In one embodiment, the method involves theadministration of a product that combines: a) an agent that activelyraises intragastric pH; and b) an NSAID that is formulated with acyclodextrin. In another embodiment, the method involves theadministration of a product that combines: a) an agent that activelyraises intragastric pH; b) an NSAID that is formulated with acyclodextrin; and c) a buffering agent. Either short or long acting acidinhibitors can be effectively used in the dosage forms. This method hasthe added benefit of being able to protect patients from othergastrointestinal ulcerogens whose effect may otherwise be enhanced bythe disruption of gastroprotective prostaglandins due to NSAID therapy.

The meloxicam formulation in an aqueous parenteral form may include abuffer to adjust the pH of an aqueous formulation, within a range ofabout 2 to about 5; about 3.5 to about 5; about 5 to about 11; about 6to about 9; about 6 to about 8; about 6 to about 7; or any other pH in arange bounded by, or between, any of these values. The meloxicamformulation in an oral form may include a buffer to adjust the pH ofstomach fluid within a range of about 2 to about 5; about 3.5 to about5; about 5 to about 11; about 6 to about 9; about 6 to about 8; about 6to about 7; or any other pH in a range bounded by, or between, any ofthese values. Examples of buffers suitable for use herein includesulfate buffers, phosphate buffers, borate buffers, carbonate buffers,citrate buffers, etc.

In some embodiments, the dosage form may be formulated for oraladministration, for example, with an inert diluent or with an ediblecarrier, or it may be enclosed in hard or soft shell gelatin capsules,compressed into tablets, or incorporated directly with the food of thediet. For oral therapeutic administration, the active compound may beincorporated with an excipient and used in the form of ingestibletablets, buccal tablets, coated tablets, troches, capsules, elixirs,dispersions, suspensions, solutions, syrups, wafers, patches, and thelike.

Tablets, troches, pills, capsules and the like may also contain one ormore of the following: a binder such as gum tragacanth, acacia, cornstarch or gelatin; an excipient, such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; a sweetening agentsuch as sucrose, lactose or saccharin; or a flavoring agent such aspeppermint, oil of wintergreen or cherry flavoring. When the unit dosageform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier. Various other materials may be present ascoating, for instance, tablets, pills, or capsules may be coated withshellac, sugar or both. A syrup or elixir may contain the activecompound, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring, such as cherry or orange flavor. Itmay be desirable for material in a dosage form or pharmaceuticalcomposition to be pharmaceutically pure and substantially non-toxic inthe amounts employed.

Some compositions or dosage forms may be a liquid, or may comprise asolid phase dispersed in a liquid.

The dosage form may further comprise a second therapeutically activeagent, such as an acid inhibitor or an analgesic.

In some embodiments, the dosage form may further comprise an acidinhibitor present in an amount effective to raise the gastric pH of apatient to at least 2, to at least 2.5, to at least 3, to at least 3.5,to at least 4, and more to at least 5, when one or more unit dosageforms are administered. The term “acid inhibitor” refers to agents thatinhibit gastric acid secretion and increase gastric pH. Specific H₂blockers, also referred to as H₂ antagonists or histamine H₂ blockers orantagonists, that may be used include but are not limited to cimetidine,ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine, famotidine,or combinations thereof.

Other agents that may be effectively used as acid inhibitors are theproton pump inhibitors such as omeprazole, esomeprazole, pantoprazole,lansoprazole, dexlansoprazole, rabeprazole, pariprazole, leminoprazoleand tenatoprazole. In some embodiments the daily dose of the acidinhibitor is about 1-200 mg, about 1-100 mg, about 1-50 mg, about 40-80mg, about 5-50 mg, about 20-40 mg, about 10-50 mg, about 10-20 mg, about20-40 mg, about 15-50 mg, about 30-60 mg, about 10 mg, about 20 mg,about 30 mg, about 40 mg or any other amount in a range bounded by, orbetween, any of these values.

Examples of particular proton pump inhibitors include esomeprazole,present in unit dosage forms in an amount of between 5 mg and 50 mg;omeprazole, present in unit dosage forms in an amount of between 5 mgand 50 mg; lansoprazole, present in unit dosage forms in an amount ofbetween 5 mg and 150 mg (and preferably at between 5 mg and 30 mg); andpantoprazole, present in unit dosage forms in an amount of between 10 mgand 200 mg. In some embodiments, the proton pump inhibitor is present inthe dosage form in an amount of about 10-30 mg, about 20-40 mg, about30-50 mg, about 40-60 mg, about 50-70 mg, about 60-80 mg, about 70-90mg, or about 80-100 mg. Recently, a newer class of acid inhibitor hasbeen developed which competes with potassium at the acid pump. Thecompounds in this class have been referred to as “reversible proton pumpinhibitors” or “acid pump antagonists” and may also be used. Examplesinclude AZD-0865, AR-H047108, CS-526, pumaprazole, revaprazan andsoraprazan (see WO9605177 and WO9605199). Other compounds in this groupare H-335/25 (AstraZeneca, Dialog file 128, accession number 020806);Sch-28080 (Schering Plough, Dialog file 128, accession number 009663);Sch-32651 (Schering Plough, Dialog file 128, accession number 006883)and SK&F-96067 (CAS Registry no. 115607-61-9).

The second therapeutically active agent may include an analgesic such asa second non-steroidal anti-inflammatory drug, an opioid, a steroid, atriptan, etc. In some embodiments, the dosage form or treatment alsofurther comprises administering a second non-steroidal anti-inflammatorydrug in an amount effective to reduce or eliminate pain or inflammation.The NSAID may include, but is not limited to, celecoxib, rofecoxib,lumiracoxib, valdecoxib, parecoxib, etoricoxib, CS-502, JTE-522,L-745,337, NS398, aspirin, acetaminophen (considered to be an NSAID forthe purposes of the present disclosure), ibuprofen, flurbiprofen,ketoprofen, naproxen, oxaprozin, etodolac, indomethacin, ketorolac,lornoxicam, meloxicam, piroxicam, droxicam, tenoxicam, nabumetone,diclofenac, meclofenamate, mefenamic acid, diflunisal, sulindac,tolmetin, fenoprofen, suprofen, benoxaprofen, aceclofenac, tolfenamicacid, oxyphenbutazone, azapropazone, phenylbutazone, or combinationsthereof. It will be understood that, for the purposes of the presentdisclosure, reference to an acid inhibitor, NSAID, or analgesic agentwill include all of the common forms of these compounds and, inparticular, their pharmaceutically acceptable salts. The amounts ofNSAIDs which are therapeutically effective may be lower in the currentembodiments than otherwise found in practice due to potential positivekinetic interaction and NSAID absorption in the presence of an acidinhibitor, and or in the presence of a buffering agent.

In other embodiments, the dosage form or treatment may further compriseadministering an opioid in an amount effective to reduce or eliminatepain or inflammation. The opioid may include, but is not limited to,(dextro)propoxyphene, A-methylfentanyl, alfentanil, allylprodine,bezitramide, buprenorphine, butorphanol, carfentanyl, desmethylprodine,dextromoramide, dezocine, diacetylmorphine, dihydrocodeinone,dihydroetorphine, dimorphone, diphenoxylate, dipipanone, etorphine,fentanyl, ketobemidone, lefetamine, levacetylmethadol, levomethorphan,levorphanol, loperamide, meperidine, meptazinol, methadone,methylmorphine, morphine, nalbuphine, nalmefene, naloxone, naltrexone,nicomorphine, ohmefentanyl, oripavine, oxycodone, oxymorphone, PEPAP,paramorphine, pentazocine, phenazocine, piritramide, prodine,remifentanil, sufentanil, tapentadol, tilidine, tramadol, orcombinations thereof.

Useful triptans may include sumatriptan, rizatriptan, naratriptan,eletriptan, donitriptan, almotriptan, frovatriptan, alvitriptan,zolmatriptan, etc. In some embodiments, the triptan comprisesrizatriptan. In some embodiments, the dosage form may contain about 1-5mg, about 2-6 mg, about 3-7 mg, about 4-8 mg, about 5-10 mg, about 6-11mg, about 7-12 mg, about 8-13 mg, about 9-14 mg, about 10-15 mg, about15-20 mg, or about 20-30 mg, of the triptan, such as rizatriptan, or anyamount in a range bounded by any of these values.

In some embodiments; a dosage form comprising the subject combinationmay contain rizatriptan in an amount of about 1-50 mg; about 1-10 mg;about 10-20 mg; about 20-30 mg; about 30-40 mg; or about 40-50 mg; about10-40 mg; about 1-35 mg; about 1-25 mg; about 1-15 mg; about 1-10 mg;about 5-20 mg; about 1-5 mg; about 2-6 mg; about 3-7 mg; about 4-8 mg;about 5-10 mg; about 6-11 mg; about 7-12 mg; about 8-13 mg; about 9-11mg; about 9-14 mg; about 10-15 mg; about 11-16 mg; about 12-17 mg; about13-18 mg; about 14-19 mg; about 15-20 mg; about 5-15 mg; about 0.5 mg;about 1 mg; about 1.5 mg; about 2 mg; about 2.5 mg; about 3 mg; about3.5 mg; about 4 mg; about 4.5 mg; about 5 mg; about 6 mg; about 7 mg;about 7.5 mg; about 8 mg, about 9 mg, about 10 mg; about 15 mg; about 20mg, about 25 mg, about 30 mg; or any amount in a range bounded by, orbetween, any of these values.

For acute migraines, the amount of meloxicam and/or rizatriptan in asingle dose, or the AUC of the meloxicam and/or rizatriptan associatedwith a single dose, is of particular interest. For example, after asingle dose, the symptoms may be relieved for an extended period oftime, such that, in the short term, repeated doses may not be needed.For more continuous conditions, including more chronic, continuous, orfrequent migraine symptoms, daily, weekly, or monthly doses may be ofparticular interest.

For any amounts of rizatriptan described herein, salt forms ofrizatriptan may be present in the amounts recited above, or amounts thatare molar equivalents to these amounts for the rizatriptan free base.For example, assuming that the molecular weight of rizatriptan free baseis 269.3 g/mol, 10 mg of rizatriptan is 37.1 mmol of rizatriptan. Thus,a molar equivalent of 10 mg of rizatriptan free base would be the massof 37.1 mmol of that salt form. For example, for the benzoate salt(mw=391.2 g/mol), the molar equivalent of 10 mg of the free base (or37.1 mmol), would be 14.5 mg. These doses may be safe for repeatedadministration, such as 1, 2, 3, or 4 times a day, or repeated at aninterval of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 4 weeks, 4-6weeks, about 1-2 months, about 6 weeks, about 2-3 months, about 3-4months, about 4-5 months, about 5-6 months, about 6-7 months, about 7-8months, about 8-9 months, about 9-10 months, about 10-11 months, about11-12 months, etc.

A pharmaceutical composition may be in the form of a tablet or capsulethat has: (a) the acid inhibitor; and/or (b) a buffering agent; and (c)the non-steroidal anti-inflammatory drug (NSAID) present in an amounteffective to reduce or eliminate pain or inflammation in a patient uponadministration of one or more of said unit dosage forms. The componentsof the pharmaceutical composition may be in an immediate or extendedrelease form individually or in total.

The term “unit dosage form” as used herein refers to a single entity fordrug administration. For example, a single tablet or capsule combiningboth an acid inhibitor and an NSAID would be a unit dosage form. A “unitdosage form” (or “unit dose form”) may also be referred to as a “fixeddosage form” (or “fixed dose form”) or “fixed dosage combination” (or“fixed dose combination”) and are otherwise interchangeable. In oneembodiment, the unit dosage form is a multilayer tablet.

In another embodiment, the unit dosage form is suitable for oraladministration to a patient. In yet another embodiment, the unit dosageform is a tablet. In still another embodiment, the unit dosage form is amultilayer tablet comprising a single core and one or more layersoutside of the core.

Some dosage forms may comprise a first layer comprising meloxicam, anSBEβCD, and a bicarbonate; and a second layer comprising a secondtherapeutically active agent and a bicarbonate.

The first layer may contain, for example, any amount of meloxicam in oneof the ranges recited above. For example, all of the meloxicam in thedosage form may be present in the first layer. The second layer maycontain all of the second therapeutically active agent, such that anyamount in the ranges recited above with respect to the secondtherapeutically active agent may apply to the second layer.

In some embodiments, the first layer contains about 10-200 mg, about50-150 mg, about 50-100 mg, about 70-120 mg, about 90-140 mg, or about100 mg of the bicarbonate, such as sodium bicarbonate, or any amount ofthe bicarbonate in a range bounded by any of these values.

In some embodiments, the second layer contains about 100-500 mg, about200-500 mg, about 300-500 mg, about 350-450 mg, about 380-420 mg, orabout 400 mg of the bicarbonate, such as sodium bicarbonate, or anyamount of the bicarbonate in a range bounded by any of these values.

In some embodiments, the pharmaceutical composition may have aneffective amount of meloxicam, a cyclodextrin, and a carbonate orbicarbonate to increase bioavailability of meloxicam. In otherembodiments, the pharmaceutical composition may have an effective amountof meloxicam, sulfobutylether-3-cyclodextrin (SBEβCD), and sodiumbicarbonate to increase bioavailability of meloxicam or reduce theT_(max) of meloxicam.

Some oral dosage forms may have enteric coatings or film coatings. Insome embodiments, a dosage form may comprise a tablet or a capsulehaving an enteric coating. In some embodiments, a dosage form maycomprise a tablet or a capsule having a film coating.

An embodiment of the present disclosure is directed to a pharmaceuticalcomposition in unit dosage form suitable for administration to apatient, comprising:

(a) esomeprazole, which may or may not be surrounded by an entericcoating;

(b) sodium or potassium bicarbonate and/or sodium or potassiumcarbonate; and

(c) meloxicam, which may or may not be formulated with a cyclodextrin,and which may or may not be surrounded by an enteric coating

An embodiment of the present disclosure is directed to a pharmaceuticalcomposition in unit dosage form suitable for administration to a patientfor treat a disease, a condition, or disorder, such as migraine,comprising:

(1) an inclusion complex of a meloxicam and a sulfobutyl etherβ-cyclodextrin (SBEβCD);

(2) a bicarbonate, such as sodium bicarbonate or potassium bicarbonate;and

(3) a triptan, such as rizatriptan.

In certain embodiments, the pharmaceutical composition results in fasterrelease or dissolution of the meloxicam from the dosage form as comparedto a dosage form containing meloxicam but not containing the acidinhibitor, or not containing the buffering agent.

A dosage form comprising a combination of rizatriptan and meloxicam (a“subject combination”) may be used to treat migraine. The subjectcombination may be used for the acute treatment of migraine. The subjectcombination may provide substantially greater and more sustainedmigraine pain relief compared to rizatriptan, meloxicam, or placebo. Thesubject combination may provide rapid relief of migraine pain. Thesubject combination may significantly reduce the use of rescuemedication compared to rizatriptan, meloxicam and placebo. The migrainepatients being treated with a combination of rizatriptan and meloxicamdescribed herein may have a history of inadequate response to prioracute treatments. The migraine patients being treated with a combinationof rizatriptan and meloxicam described herein may have allodynia, suchas cutaneous allodynia. The migraine patients being treated with acombination of rizatriptan and meloxicam described herein may havesevere pain intensity. The migraine patients being treated with acombination of rizatriptan and meloxicam described herein may haveobesity. The migraine patients being treated with a combination ofrizatriptan and meloxicam described herein may have morning migraine.The migraine patients being treated with a combination of rizatriptanand meloxicam described herein may have a total mean score of theMigraine Treatment Optimization Questionnaire (mTOQ-4) of less than 7,such as 1-2, 2-3, 3-4, 4-5, 5-6, or 6-7. The migraine patients beingtreated with a combination of rizatriptan and meloxicam described hereinmay have allodynia, such as cutaneous allodynia, severe pain intensity,obesity, morning migraine, a total mean score of the mTOQ-4 of less than7, and a history of inadequate response to prior acute treatments. Adosage form comprising a combination of rizatriptan and meloxicamdescribed herein is safe and well tolerated in the migraine patientsbeing treated.

A dosage form comprising a combination of rizatriptan and meloxicamdescribed herein may provide rapid relief of migraine pain in less than15 minutes, about 15 minutes, less than 30 minutes, 15-30 minutes, lessthan 1 hour, 0.5-0.75 hour, or 0.75-1 hour post dose. The combination ofrizatriptan and meloxicam described herein may provide relief ofmigraine pain that is numerically greater than rizatriptan at less than15 minutes, about 5 minutes, about 5-10 minutes, about 10-15 minutes,about 15 minutes, about 15-30 minutes, about 30-45 minutes, about 45-60minutes, about 1-1.5 hours, about 1.5-2 hours, about 2-2.5 hours, about2.5-3 hours, about 3-3.5 hours, about 3.5-4 hours, about 4-5 hours,about 5-6 hours, about 6-8 hours, about 8-10 hours, about 10-12 hours,about 12-24 hours, about 24-48 hours, or longer, post dose. Thepercentage of migraine patients reporting pain relief with the treatmentof a combination of rizatriptan and meloxicam described herein may be1-100%, 3-100%, 4-100%, 5-100%, 3-5%, 5-10%, 10-20%, 20-30%, 30-40%,40-50%, 50-60%, 60-70%, 70-80%, 80-90%, 90-95%, or 95-100%.

The migraine patients receiving a dosage form comprising a combinationof rizatriptan and meloxicam described herein (“subject combination”)may achieve pain freedom at less than 2 hours, about 2 hours, about 2-3hours, about 3-4 hours, about 4-6 hours, about 6-8 hours, about 8-10hours, about 10-12 hours, about 12-16 hours, about 16-20 hours, about20-24 hours, about 24-30 hours, about 30-36 hours, about 36-40 hours,about 40-44 hours, about 44-48 hours, or longer post dose.

The percentage of migraine patients achieving pain freedom increasesover time after receiving a dose of a combination of rizatriptan andmeloxicam described herein. For example, at 2 h post dose, thepercentage of migraine patients achieving pain freedom may be about15-25%, about 15-20%, about 20%, about 20-25%. At 4 h post dose, thepercentage of migraine patients achieving pain freedom may be about30-50%, about 30-40%, about 40%, about 40-45%, about 45-47%, about47-50%. At 12 h post dose, the percentage of migraine patients achievingpain freedom may be about 45-70%, about 45-50%, about 50-55%, about55-60%, about 56-57%, about 60-65%, about 65-70%. At 16 h post dose, thepercentage of migraine patients achieving pain freedom may be about45-70%, about 45-50%, about 50-55%, about 55-60%, about 58-59%, about60-65%, about 65-70%. The combination of rizatriptan and meloxicamdescribed herein may provide significant improvement over rizatriptan inpain freedom in the migraine patients. There may be about 2-10%, 2-3%,3-5%, 5-7%, 6-7%, 7-8%, 8-9%, or 9-10% more migraine patients receivingthe combination of rizatriptan and meloxicam described herein achievingpain freedom than the migraine patients receiving rizatriptan at 2-16hours post dose with an improvement of about 10-25%, 10-15%, 14-15%,15-16%, 16-17%, 17-18%, 18-19%, 19-20%, 20-21%, or 21-25%. For example,at 4 hours post dose, if about 40% migraine patients receiving thesubject combination achieve pain freedom, while 33% migraine patientsreceiving rizatriptan achieve pain freedom, then the improvement of thesubject combination is about 21% [((40-33)/33)×100%]. The improvementwith the subject combination over meloxicam may be bigger than overrizatriptan in migraine patients achieving pain freedom. For example,The improvement with the subject combination over meloxicam in migrainepatients achieving pain freedom may be about 25-75%, 25-30%, 27-28%,28-29%, 30-40%, 40-50%, 50-60%, 55-50%, 60-70%, 65-75%, or 70-75% at2-16 hours post dose.

There may be at least 50%, at least 60%, at least 70%, at least 80%,about 70-80%, about 80-90%, about 90-95%, about 80% of migraine patientsreceiving the combination of rizatriptan and meloxicam described herein(“subject combination”) achieving pain freedom at 2 hours may maintainit through 24 hours post dose. The increase of the number of migrainepatients (or improvement) achieving sustained pain freedom from 2-24hours post dose of the subject combination may be about 35-55%, about35-40%, about 40-45%, about 45-50%, or about 50-55% as compared toadministering rizatriptan. The increase of the number of migrainepatients (or improvement) achieving sustained pain freedom from 2-24hours post dose of the subject combination may be about 100-165%, about100-110%, about 110-120%, about 120-130%, about 130-140%, about140-150%, about 150-160%, or about 160-165% as compared to administeringmeloxicam.

The increase of the number of migraine patients (or improvement)achieving sustained pain relief from 2-24 hours post dose of the subjectcombination may be about 15-30%, about 15-20%, about 20-25%, about25-30%, about 20-22%, or about 21% as compared to administeringrizatriptan. The increase of the number of migraine patients (orimprovement) achieving sustained pain relief from 2-24 hours post doseof the subject combination may be about 20-35%, about 20-25%, about25-30%, about 30-35%, about 25-26%, about 26-27%, about 27-28%, about28-30%, or about 27% as compared to administering meloxicam.

There may be at least 50%, at least 60%, at least 70%, at least 80%,about 70-80%, about 80-90%, about 90-95%, or about 77% of migrainepatients receiving the combination of rizatriptan and meloxicamdescribed herein (“subject combination”) achieving pain freedom at 2hours may maintain it through 48 hours post dose. The increase of thenumber of migraine patients (or improvement) achieving sustained painfreedom from 2-48 hours post dose of the subject combination may beabout 60-90%, about 60-70%, about 70-75%, about 75-80%, about 80-90%, orabout 75% as compared to administering rizatriptan. The increase of thenumber of migraine patients (or improvement) achieving sustained painfreedom from 2-48 hours post dose of the subject combination may beabout 70-110%, about 70-80%, about 80-90%, about 90-100%, about100-110%, or about 90% as compared to administering meloxicam.

The increase of the number of migraine patients (or improvement)achieving sustained pain relief from 2-48 hours post dose of the subjectcombination may be about 20-35%, about 20-25%, about 25-30%, about30-35%, about 25-26%, about 26-27%, about 27-28%, about 28-20%, or about27% as compared to administering rizatriptan. The increase of the numberof migraine patients (or improvement) achieving sustained pain relieffrom 2-48 hours post dose of the subject combination may be about15-30%, about 15-20%, about 20-25%, about 25-30%, about 20-21%, about21-22%, about 22-23%, about 23-24%, about 24-25%, or about 23% ascompared to administering meloxicam.

There may be at least 50%, at least 60%, at least 70%, about 60-65%,about 65-70%, about 70-75%, about 75-80%, about 80-85%, about 85-90%,about 90-95%, or about 77% of migraine patients receiving thecombination of rizatriptan and meloxicam described herein (“subjectcombination”) may not require rescue medication. The decrease of thenumber of migraine patients who took rescue medication through 24 hourspost dose of the subject combination may be about 35-60%, about 35-40%,about 40-45%, about 45-50%, about 50-55%, about 55-60%, about 47-48%, orabout 47% as compared to administering placebo. The decrease of thenumber of migraine patients who took rescue medication through 24 hourspost dose of the subject combination may be about 25-45%, about 25-30%,about 30-35%, about 35-40%, about 40-45%, about 34-36%, or about 35% ascompared to administering meloxicam. The decrease of the number ofmigraine patients who took rescue medication through 24 hours post doseof the subject combination may be about 25-40%, about 25-30%, about30-35%, about 35-40%, about 33-35%, or about 34% as compared toadministering rizatriptan.

The following embodiments are contemplated:

Embodiment 1

An inclusion complex of meloxicam in a cyclodextrin.

Embodiment 2

A dosage form comprising: 1) the inclusion complex of embodiment 1, or2) meloxicam and a carbonate or a bicarbonate.

Embodiment 3

The dosage form of embodiment 2 comprising the inclusion complex,wherein the cyclodextrin comprises substituted β-cyclodextrin.

Embodiment 4

The dosage form of embodiment 3, wherein the substituted β-cyclodextrinis a sulfobutyl ether β-cyclodextrin (SBEβCD) or hydroxypropylβ-cyclodextrin (HPBCD).

Embodiment 5

The dosage form of embodiment 4, wherein the cyclodextrin is the SBEβCD.

Embodiment 6

The dosage form of embodiment 5, wherein the SBEβCD has about 6 to about7 sulfobutyl ether groups for each molecule of β-cyclodextrin.

Embodiment 7

The dosage form of embodiment 6, wherein the meloxicam and the SBEβCDhave a molar ratio of about 0.8 to about 1.2.

Embodiment 8

The dosage form of embodiment 6, wherein the meloxicam and the SBEβCDhave a molar ratio of about 1.

Embodiment 9

The dosage form of embodiment 2, 3, 4, 5, 6, 7, or 8, comprising abicarbonate.

Embodiment 10

The dosage form of embodiment 9, wherein the bicarbonate comprisessodium bicarbonate.

Embodiment 11

The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, or 10, which is anoral dosage form.

Embodiment 12

The dosage form of embodiment 2, 3, 4, 5, 6, 9, 10, or 11, wherein about50 mg to about 200 mg of SBEβCD is present in the dosage form.

Embodiment 13

The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12,wherein the carbonate or bicarbonate is present in an amount in a rangeof about 400 mg to about 600 mg.

Embodiment 14

The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13,wherein the T_(max) of meloxicam is decreased as compared to a dosageform not having a carbonate, a bicarbonate, or a cyclodextrin.

Embodiment 15

The method of embodiment 14, wherein the T_(max) of meloxicam isachieved in the patient at a time in a range of about 10 minutes toabout 180 minutes after administration.

Embodiment 16

The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, or 15, having an oral bioavailability of meloxicam that is higherthan a dosage form not having a carbonate, a bicarbonate, or acyclodextrin.

Embodiment 17

The dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, or 20, further comprising an acid inhibitor.

Embodiment 18

The dosage form of embodiment 17, wherein the acid inhibitor is a protonpump inhibitor.

Embodiment 19

The dosage form of embodiment 18, wherein the proton pump inhibitor isesomeprazole.

Embodiment 20

The dosage form of embodiment 19, wherein about 30 mg to about 50 mg ofesomeprazole is present in the dosage form.

Embodiment 21

A method of administering meloxicam orally, comprising orallyadministering a dosage form of embodiment 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 to a patient in need oftreatment.

Embodiment 22

The method of embodiment 21, wherein the dosage form is administered totreat pain.

Embodiment 23

The method of embodiment 21, wherein the dosage form is administered totreat inflammatory pain.

Embodiment 24

The method of embodiment 21, wherein the dosage form is administered totreat osteoarthritis, rheumatoid arthritis, or juvenile rheumatoidarthritis.

Embodiment 25

A method of administering meloxicam intravenously, comprisingintravenously administering a dosage form of embodiment 2, 3, 4, 5, 6,7, 8, 9, 10, 12, 13, 14, or 15, to a patient in need of treatment.

Embodiment 26

The method of embodiment 21, wherein the dosage form is administered totreat migraine.

Embodiment 27

A dosage form comprising: 1) the inclusion complex of meloxicam in acyclodextrin, 2) a bicarbonate, and 3) a triptan.

Embodiment 28

The dosage form of embodiment 27, wherein the triptan is rizatriptan.

Embodiment 29

The dosage form of embodiment 27, wherein the bicarbonate comprisessodium bicarbonate.

Embodiment 30

The dosage form of embodiment 27, wherein the cyclodextrin is asulfobutyl ether β-cyclodextrin (SBEβCD).

Embodiment 31

The dosage form of embodiment 30, wherein the SBEβCD has about 6 toabout 7 sulfobutyl ether groups for each molecule of β-cyclodextrin.

Embodiment 32

The dosage form of embodiment 30, wherein the meloxicam and the SBEβCDhave a molar ratio of about 0.8 to about 1.2.

Embodiment 33

The dosage form of embodiment 32, wherein the meloxicam and the SBEβCDhave a molar ratio of about 1.

Embodiment 34

The dosage form of embodiment 27, 28, 29, 30, 31, 32, or 33, which is anoral dosage form.

Embodiment 35

The dosage form of embodiment 27, 28, 29, 30, 31, 32, 33, or 34, whereinabout 50 mg to about 200 mg of SBEβCD is present in the dosage form.

Embodiment 36

The dosage form of embodiment 27, 28, 29, 30, 31, 32, 33, 34, or 35,wherein the bicarbonate is present in an amount of about 400 mg to about1000 mg.

Embodiment 37

A method of treating migraine, comprising administering a dosage formcomprising meloxicam, at least 400 mg of a bicarbonate, and arizatriptan to a human being suffering from migraine; wherein theT_(max) of rizatriptan in the dosage form is shorter than that in areference dosage form comprising a) same amount of rizatriptan; 2) nomeloxicam; and c) no bicarbonate.

Embodiment 38

A method of treating migraine, comprising administering meloxicam andabout 8 mg to about 13 mg of rizatriptan, based upon the weight of therizatriptan in the free base form, to a human being who is sufferingfrom an acute attack of migraine pain or migraine aura, wherein themeloxicam and the rizatriptan are administered within about 30 minutesof one another, wherein administering the meloxicam to the human beingresults in a T_(max) of meloxicam of 110 minutes or less, and an AUC₀₋₂₄of meloxicam of about 30 μg·hr/mL to about 50 μg·hr/mL.

Embodiment 39

A pharmaceutical dosage form comprising: 1) about 0.028 mmol to about0.085 mmol of meloxicam in a free acid or a salt form, 2) about 0.019mmol to about 0.056 mmol of rizatriptan in a free base or a salt form,3) about 100 mg to about 175 mg of a sulfobutylether-β-cyclodextrin(SBEβCD), and 4) about 400 mg to about 600 mg of sodium bicarbonate.

Embodiment 40

A method of treating migraine comprising: selecting a human migrainepatient with a history of inadequate response to prior migrainetreatments, and orally administering a dosage form to the migrainepatient, wherein the dosage form comprises a combination of: 1)meloxicam (optionally in a complex with a sulfobutyl etherβ-cyclodextrin (SBEβCD)), 2) a bicarbonate, and 3) a rizatriptan.

Embodiment 41

The method of embodiment 40, wherein the human migraine patientexperiences relief of the migraine pain as a result of orallyadministering the dosage form to the migraine patient.

Embodiment 42

The method of embodiment 40 or 41, wherein the human migraine patient isfree of migraine pain two hours after the dosage form is orallyadministered to the human migraine patient.

Embodiment 43

The method of embodiment 40, 41, or 42, wherein the migraine patientexperiences a reduction in nausea as a result of orally administeringthe dosage form to the migraine patient.

Embodiment 44

The method of embodiment 40, 41, 42, or 43, wherein the human migrainepatient is free of nausea two hours after the dosage form is orallyadministered to the human migraine patient.

Embodiment 45

The method of embodiment 40, 41, 42, 43, or 44, wherein the migrainepatient experiences a reduction in photophobia as a result of orallyadministering the dosage form to the migraine patient.

Embodiment 46

The method of embodiment 40, 41, 42, 43, 44, or 45, wherein the humanmigraine patient is free of photophobia two hours after the dosage formis orally administered to the human migraine patient.

Embodiment 47

The method of embodiment 40, 41, 42, 43, 44, 45, or 46, wherein themigraine patient experiences a reduction in phonophobia as a result oforally administering the dosage form to the migraine patient.

Embodiment 48

The method of embodiment 40, 41, 42, 43, 44, 45, 46, or 47, wherein thehuman migraine patient is free of phonophobia two hours after the dosageform is orally administered to the human migraine patient.

Embodiment 49

The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, or 48, whereinthe dosage form contains 400 mg to 600 mg of the bicarbonate.

Embodiment 50

The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49,wherein the dosage form contains about 5 mg to about 50 mg of meloxicam.

Embodiment 51

The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50,wherein the dosage form contains about 50 mg to about 200 mg of theSBEβCD.

Embodiment 52

The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or51, wherein the dosage form is a solid oral dosage form having a shorterT_(max) of meloxicam in the human being than a reference dosage formthat: 1) contains the same amount of meloxicam, 2) does not contain anSBEβCD, and 3) does not contain a bicarbonate.

Embodiment 53

The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,or 52, wherein about 1 mg to about 50 mg of the rizatriptan is presentin the oral dosage form based upon the weight of the rizatriptan in thefree base form.

Embodiment 54

The method of embodiment 53, wherein the rizatriptan is present in asalt form in an amount that is a molar equivalent of about 10 mg of therizatriptan in the free base form.

Embodiment 55

The method of embodiment 53 or 54, wherein the rizatriptan is present asrizatriptan benzoate.

Embodiment 56

The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, or 55, wherein the oral dosage form contains about 10 mg toabout 30 mg of meloxicam.

Embodiment 57

The method of embodiment 56, wherein the oral dosage form contains about20 mg of meloxicam.

Embodiment 58

The method of embodiment 56, wherein the oral dosage form contains about15 mg of meloxicam.

Embodiment 59

The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, or 58, wherein the SBEβCD has about 6 to about 7sulfobutyl ether groups for each molecule of β-cyclodextrin.

Embodiment 60

The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, or 59, wherein the oral dosage form containsabout 50 mg to about 150 mg of the SBEβCD.

Embodiment 61

The method of embodiment 60, wherein the oral dosage form contains about100 mg of the SBEβCD.

Embodiment 62

The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, 59, 60, or 61, wherein the molar ratio ofthe SBEβCD to meloxicam is about 0.5 to about 2.

Embodiment 63

The method of embodiment 62, wherein the molar ratio of the SBEβCD tomeloxicam is about 0.8 to about 1.2.

Embodiment 64

The method of embodiment 62, wherein the molar ratio of the SBEβCD tomeloxicam is about 1.

Embodiment 65

The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, or 64, wherein the oraldosage form contains about 10 mg to about 40 mg of meloxicam, and about5 mg to about 50 mg of rizatriptan.

Embodiment 66

The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65, wherein theoral dosage form contains SBEβCD that is in a weight ratio torizatriptan that is within a range of about 1 to about 100.

Embodiment 67

The method of embodiment 66, wherein the oral dosage form containsSBEβCD that is in a weight ratio to rizatriptan that is about 10.

Embodiment 68

The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, or 67,wherein the bicarbonate comprises sodium bicarbonate.

Embodiment 69

The method of embodiment 68, wherein the oral dosage form contains 500mg of sodium bicarbonate.

Embodiment 70

The method of embodiment 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, or69, wherein the oral dosage form has been shown to have a median T_(max)of meloxicam that is less than about 90 minutes in fasted humansubjects.

Embodiment 71

The method of embodiment 70, wherein the oral dosage form has been shownto have a median T_(max) of meloxicam that is less than about 2 hours infasted human subjects.

Embodiment 72

The method of embodiment 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, 70, or 71, wherein the oral dosage form has beenshown to have faster time to therapeutic plasma concentration in thehuman being as compared to the reference dosage form.

Embodiment 73

A method of treating migraine comprising: selecting a human migrainepatient with a history of inadequate response to prior migrainetreatments, and orally administering a dosage form to the migrainepatient, wherein the dosage form comprises a combination of: 1)meloxicam (optionally in a complex with a sulfobutyl etherβ-cyclodextrin (SBEβCD)), 2) a bicarbonate, and 3) a rizatriptan,wherein the human migraine patient experiences relief of the migrainepain as a result of orally administering the dosage form to the migrainepatient.

Embodiment 74

A method of treating migraine comprising: selecting a human migrainepatient with a history of inadequate response to prior migrainetreatments, and orally administering a dosage form to the migrainepatient, wherein the dosage form comprises a combination of: 1)meloxicam (optionally in a complex with a sulfobutyl etherβ-cyclodextrin (SBEβCD)), 2) a bicarbonate, and 3) a rizatriptan,wherein the human migraine patient is free of migraine pain two hoursafter the dosage form is orally administered to the human migrainepatient.

Embodiment 75

A method of treating migraine comprising: selecting a human migrainepatient with a history of inadequate response to prior migrainetreatments, and orally administering a dosage form to the migrainepatient, wherein the dosage form comprises a combination of: 1)meloxicam (optionally in a complex with a sulfobutyl etherβ-cyclodextrin (SBEβCD)), 2) a bicarbonate, and 3) a rizatriptan,wherein the migraine patient experiences a reduction in nausea as aresult of orally administering the dosage form to the migraine patient.

Embodiment 76

A method of treating migraine comprising: selecting a human migrainepatient with a history of inadequate response to prior migrainetreatments, and orally administering a dosage form to the migrainepatient, wherein the dosage form comprises a combination of: 1)meloxicam (optionally in a complex with a sulfobutyl etherβ-cyclodextrin (SBEβCD)), 2) a bicarbonate, and 3) a rizatriptan,wherein the human migraine patient is free of nausea two hours after thedosage form is orally administered to the human migraine patient.

Embodiment 77

A method of treating migraine comprising: selecting a human migrainepatient with a history of inadequate response to prior migrainetreatments, and orally administering a dosage form to the migrainepatient, wherein the dosage form comprises a combination of: 1)meloxicam (optionally in a complex with a sulfobutyl etherβ-cyclodextrin (SBEβCD)), 2) a bicarbonate, and 3) a rizatriptan,wherein the migraine patient experiences a reduction in photophobia as aresult of orally administering the dosage form to the migraine patient.

Embodiment 78

A method of treating migraine comprising: selecting a human migrainepatient with a history of inadequate response to prior migrainetreatments, and orally administering a dosage form to the migrainepatient, wherein the dosage form comprises a combination of: 1)meloxicam (optionally in a complex with a sulfobutyl etherβ-cyclodextrin (SBEβCD)), 2) a bicarbonate, and 3) a rizatriptan,wherein the human migraine patient is free of photophobia two hoursafter the dosage form is orally administered to the human migrainepatient.

Embodiment 79

A method of treating migraine comprising: selecting a human migrainepatient with a history of inadequate response to prior migrainetreatments, and orally administering a dosage form to the migrainepatient, wherein the dosage form comprises a combination of: 1)meloxicam (optionally in a complex with a sulfobutyl etherβ-cyclodextrin (SBEβCD)), 2) a bicarbonate, and 3) a rizatriptan,wherein the migraine patient experiences a reduction in phonophobia as aresult of orally administering the dosage form to the migraine patient.

Embodiment 80

A method of treating migraine comprising: selecting a human migrainepatient with a history of inadequate response to prior migrainetreatments, and orally administering a dosage form to the migrainepatient, wherein the dosage form comprises a combination of: 1)meloxicam (optionally in a complex with a sulfobutyl etherβ-cyclodextrin (SBEβCD)), 2) a bicarbonate, and 3) a rizatriptan,wherein the human migraine patient is free of phonophobia two hoursafter the dosage form is orally administered to the human migrainepatient.

Embodiment 81

A method of more rapidly improving migraine pain relief associated withrizatriptan therapy, comprising: orally administering to a human beingin need thereof, a combination of: 1) a complex of a meloxicam and asulfobutylether-β-cyclodextrin, 2) a bicarbonate, and 3) a rizatriptan,wherein one hour after the combination is administered, the human beingexperiences a greater reduction in migraine pain than the human beingwould experience one hour after the same amount of the rizatriptan isadministered alone.

Embodiment 82

A method of relieving migraine pain, comprising: orally administering toa human being in need thereof, a combination of: 1) a complex ofmeloxicam and a sulfobutylether-β-cyclodextrin, 2) a bicarbonate, and 3)a rizatriptan, wherein the combination is orally administered when thehuman being is suffering from moderate to severe migraine pain of anacute migraine, wherein two hours after the combination is administered,the human being experiences a greater reduction in the human being'smost bothersome symptom than the human being would experience two hoursafter the same amount of the rizatriptan is administered alone.

Embodiment 83

A method of relieving migraine pain, comprising: orally administering toa human being in need thereof, a combination of: 1) a complex ofmeloxicam and a sulfobutylether-β-cyclodextrin, 2) a bicarbonate, and 3)a rizatriptan, wherein the combination is orally administered when thehuman being is suffering from moderate to severe migraine pain of anacute migraine, wherein the human being suffers from migraine withcutaneous allodynia, wherein two hours after the combination is orallyadministered, the human being experiences a greater reduction in themigraine pain than the human being would experience two hours after thesame amount of the meloxicam is administered alone.

Embodiment 84

A method of relieving migraine pain, comprising: orally administering toa human being in need thereof, a combination of: 1) a complex ofmeloxicam and a sulfobutylether-β-cyclodextrin, 2) a bicarbonate, and 3)a rizatriptan, wherein the combination is orally administered when thehuman being is suffering from severe migraine pain of an acute migraine,wherein two hours after the combination is orally administered, thehuman being experiences a greater reduction in the migraine pain thanthe human being would experience two hours after the same amount of themeloxicam is administered alone.

Embodiment 85

The method of embodiment 81, 82, 83, or 84, wherein the migraine pain isaccompanied by disturbed vision.

Embodiment 86

The method of embodiment 85, wherein the human being achieves absence ofthe disturbed vision at 2 hours after the combination is orallyadministered.

Example 1

The effect of varying amounts of potassium carbonate (K₂CO₃) and sodiumbicarbonate (NaHCO₃) on the pH of acidic media was tested. The acidicmedia was chosen to simulate gastric conditions. K₂CO₃ or NaHCO₃ wasadded to 50 mL of a 0.01 N HCl solution (pH 2). The pH of the solutionwas measured after addition of the K₂CO₃ or NaHCO₃. Deionized water (240mL) was then added to the mixture and pH was measured again. The resultsare shown in Tables 1-4.

TABLE 1 Results with K₂CO₃ (0.01N HCl) K₂CO₃ (mg) pH 25 2.84 35 6.29 458.05 50 8.29 100 9.43 200 10.14 300 10.39 400 10.55 450 10.58

TABLE 2 Results with K₂CO₃ (0.01N HCl + Water) K₂CO₃ (mg) pH 200 10.27300 10.46 400 10.57 450 10.63

TABLE 3 Results with NaHCO₃ (0.01N HCl) NaHCO₃ (mg) pH 200 5.28 300 5.90400 6.44 450 6.86 500 8.23 750 8.30 1000 8.36

TABLE 4 Results with NaHCO₃ (0.01N HCl + Water) NaHCO₃ (mg) pH 200 5.41300 5.89 400 6.11 450 6.46 500 8.33 750 8.54 1000 8.60

Example 2

Tablets containing meloxicam and combinations of asulfobutylether-β-cyclodextrin (SBEβCD) (a cyclodextrin, containingabout 6 to about 7 sulfobutyl ether groups for each molecule ofβ-cyclodextrin), K₂CO₃, or NaHCO₃ were manufactured and tested fordissolution. Tablets containing meloxicam alone (MOBIC®) were purchasedand also tested for dissolution. The tested tablets are listed in Table5. Meloxicam in the form of meloxicam/SBEβCD inclusion complexes wasused in the tablets containing meloxicam and SBEβCD. The inclusioncomplexes were formed by mixing meloxicam and SBEβCD in an aqueouspH-adjusted solution. The pH of the solution was adjusted usingbuffering agents. The resulting soluble meloxicam/SBEβCD inclusioncomplexes were then spray dried. This spray-dried dispersion was used inthe manufacture of the tablets containing SBEβCD.

TABLE 5 Tablets Tablet A 15 mg meloxicam + 25 mg K₂CO₃ Tablet B 15 mgmeloxicam + 50 mg K₂CO₃ Tablet C 15 mg meloxicam + 100 mg K₂CO₃ Tablet D15 mg meloxicam + 150 mg K₂CO₃ Tablet E 15 mg meloxicam + 500 mg NaHCO₃Tablet F 15 mg meloxicam + 100 mg SBEβCD Tablet G 15 mg meloxicam + 100mg SBEβCD + 25 mg K₂CO₃ Tablet H 15 mg meloxicam + 100 mg SBEβCD + 50 mgK₂CO₃ Tablet I 15 mg meloxicam + 100 mg SBEβCD + 100 mg K₂CO₃ Tablet J15 mg meloxicam + 100 mg SBEβCD + 150 mg K₂CO₃ Tablet K 15 mgmeloxicam + 100 mg SBEβCD + 500 mg NaHCO₃ Tablet L 15 mg meloxicam(MOBIC ®)

Dissolution testing in acidic medium (chosen to simulate gastricconditions) was performed by placing the tablets in a 0.01 N HClsolution, at an agitation rate of 75 RPM, and vessel temperature ofapproximately 37° C. The results are presented in Tables 6 and in FIGS.1-10. Results at various time points (0, 15, 30, 45, 60, 90, and 120minutes) are presented as percent (%) of meloxicam dissolved.

TABLE 6 Dissolution Results 0 15 30 45 60 90 120 mins mins mins minsmins mins mins Tablet A 0% 23% 17% 15% 13% 12% 11% Tablet B 0% 27% 20%17% 16% 17% 15% Tablet C 0% 31% 26% 25% 24% 23% 21% Tablet D 0% 30% 26%25% 24% 23% 22% Tablet E 0% 50% 66% 77% 84% 92% 95% Tablet F 0% 26% 17%14% 12% 11% 10% Tablet G 0% 48% 39% 26% 20% 16% 14% Tablet H 0% 44% 30%22% 17% 16% 13% Tablet I 0% 32% 33% 27% 21% 16% 15% Tablet J 0% 26% 27%19% 15% 12% 11% Tablet K 0% 85% 86% 86% 86% 86% 86% Tablet L 0%  2%  2% 2%  2%  2%  2%

Dissolution of meloxicam was greater with the tablets containing variouscombinations of meloxicam and SBEβCD, K₂CO₃, or NaHCO₃, as compared totablets containing meloxicam alone. For example, after 120 minutes,dissolution of meloxicam tablets containing NaHCO₃ was 95% as comparedto 2% for tablets containing meloxicam alone.

Dissolution of meloxicam increases with increasing amounts of K₂CO₃ inthe absence of SBEβCD. However, in the presence of SBEβCD, increasingamounts of K₂CO₃ did not appear to increase meloxicam dissolution. Atthe highest dose of potassium carbonate tested, meloxicam dissolution inthe presence of SBEβCD was reduced by approximately 50% as compared tomeloxicam dissolution in the absence of SBEβCD at 120 minutes.

Dissolution of meloxicam with NaHCO₃ was significantly greater than thatobserved with the highest dose of K₂CO₃ at 15 minutes (50% versus 30%),and at 120 minutes (92% versus 23%). Meloxicam dissolution in thepresence of SBEβCD was also significantly greater with NaHCO₃ ascompared to the highest dose of K₂CO₃ at 15 minutes (85% versus 26%),and at 120 minutes (86% versus 12%). NaHCO₃ in the presence of SBEβCDincreased meloxicam dissolution more at 15 minutes as compared topotassium carbonate, which resulted in a reduction in dissolution.

Example 3

A bilayer tablet containing 1) an inclusion complex of SBEβCD withmeloxicam, prepared as described below, and 2) sodium bicarbonate wasprepared (SBEβCD-Meloxicam/Bicarbonate). The first layer contained aninclusion complex of 15 mg meloxicam and 100 mg SBEβCD, and 100 mg ofsodium bicarbonate. The second layer contained 40 mg of esomeprazole and400 mg of sodium bicarbonate.

A total of 20 human subjects were randomly assigned in a 1:1 ratio totreatment with the SBEβCD-Meloxicam/Bicarbonate tablets described aboveor Mobic® tablets (15 mg meloxicam), once daily for 6 days under fastingconditions.

On the first day of dosing, plasma samples were collected forconcentration analysis of meloxicam at several time points.Concentrations of meloxicam were determined using LC-MS/MS.Pharmacokinetic parameters were calculated. The results are depicted inFIG. 11.

The median T_(max) for meloxicam, the trial's primary endpoint, was 9times faster for the SBEβCD-Meloxicam/Bicarbonate tablets as compared toMobic® (0.5 hour versus 4.5 hours respectively, p<0.0001).

The SBEβCD-Meloxicam/Bicarbonate tablets also demonstrated higher meanmaximum plasma concentration (C_(max)) (p=0.0018), faster time totherapeutic plasma concentration (p<0.0001), and faster time tohalf-maximal plasma concentration (p<0.0001) as compared to Mobic®.

Meloxicam in the form of meloxicam/SBEβCD inclusion complexes was usedin the tablets containing meloxicam and SBEβCD. The inclusion complexeswere formed by mixing meloxicam and SBEβCD in an aqueous pH-adjustedsolution. The pH of the solution was adjusted using buffering agents.The resulting soluble meloxicam/SBEβCD inclusion complexes were thenspray dried. This spray-dried dispersion was used in the manufacture ofthe tablets containing SBEβCD.

Example 4

A monolayer tablet containing 1) the inclusion complex of SBEβCD withmeloxicam; 2) rizatriptan; and 3) sodium bicarbonate was prepared(SBEβCD-Meloxicam/rizatriptan/Bicarbonate). The monolayer tabletcontained 20 mg of meloxicam, 10 mg of rizatriptan, and 500 mg of sodiumbicarbonate. The inclusion complex was the same as the inclusion complexof Example 3.

Dissolution testing of the tablets in acidic medium (chosen to simulategastric conditions) was performed by placing the tablets in a 0.01 N HClsolution, at an agitation rate of 75 RPM, and vessel temperature ofapproximately 37° C. The results are presented in Table 7. Results atvarious time points (0, 15, 30, 45, 60, 90, and 120 minutes) arepresented as percent (%) of meloxicam, and percent (%) of rizatriptandissolved.

TABLE 7 Dissolution Results Time-point (minutes) 0 15 30 45 60 90 120min min min min min min min Rizatriptan 0% 89% 102% 103% 103% 103% 103%Meloxicam 0% 79%  92%  93%  93%  93%  94%

As shown in Table 7, the dissolution results of the tablets in Example 4are very similar to the dissolution result of Example 3. Therefore, weexpected the pharmacokinetic properties, including bioavailability,T_(max) of meloxicam, etc., of the tablets in Example 4 to be similar tothose described in Example 3 and FIG. 11. This expectation turned out tobe correct, as shown in the examples below.

Example 5

The monolayer tablet of Example 4 was administered to six humansubjects. On the first day of dosing, plasma samples were collected forconcentration analysis of rizatriptan at several time points.Concentrations of rizatriptan and meloxicam were determined usingLC-MS/MS. Pharmacokinetic parameters were calculated. The results formeloxicam were comparable to those reported for the bilayer dosage formof Example 3. The median T_(max) of rizatriptan was 0.75 hours and themean C_(max) of rizatriptan was 20.710 ng/mL. By comparison, thereported T_(max) of the commercial rizatriptan dosage form, Maxalt®, is1.0-1.5 hours.

Example 6

A Phase 1, randomized, single-dose, parallel-group clinical study wasconducted to evaluate the PK, safety and tolerability of 1) acombination of meloxicam (20 mg), rizatriptan (10 mg), SBEβCD, andsodium bicarbonate (meloxicam/rizatriptan), as compared to 2) andMaxalt® (10 mg rizatriptan), in healthy human volunteers after oraladministration under fasted conditions. A total of 20 healthy, adultmale or female volunteers were randomized in a 1:1 ratio to receive asingle dose of meloxicam/rizatriptan, or Maxalt® (10 mg rizatriptan).

Blood samples for PK analysis were collected pre dose and at multipletime points post dose. The pre-specified primary endpoint was T_(thera),the time to reach a therapeutic plasma concentration of meloxicam,defined as the C_(avg) of meloxicam after administration of the highestapproved dose (15 mg) of standard meloxicam, which is approximately 1000ng/mL. PK results for the rizatriptan component of meloxicam/rizatriptanwere compared to those for Maxalt® (rizatriptan).

PK results for the meloxicam (20 mg) component of meloxicam/rizatriptanfrom this trial were compared to PK results for Mobic® (15 mg meloxicam)from Example 3.

Phase 1 Results

Meloxicam was rapidly absorbed after oral administration ofmeloxicam/rizatriptan (20 mg meloxicam/10 mg rizatriptan), with a mediantime to therapeutic plasma concentration (T_(thera)) of 17 minutes, theprimary endpoint (FIG. 12 and Table 8). Median T_(max) was 1 hourcompared to 4.5 hours for 15 mg standard meloxicam (Mobic®). The veryshort T_(max) suggests the potential for meloxicam/rizatriptan to haverapid onset of action in treating migraine. Mean plasma eliminationhalf-life (T_(1/2)) for meloxicam was 18.2 hours after administration ofmeloxicam/rizatriptan, which compares to 21.5 hours for standardmeloxicam. The long elimination half-life suggests the potential formeloxicam/rizatriptan to enhanced and sustained efficacy, and to reducemigraine pain recurrence.

TABLE 8 Meloxicam Pharmacokinetic Parameters for Meloxicam/RizatriptanAUC_(0-inf) T_(1/2) el C_(max) T_(max) T_(thera) Statistic (ng · hr/mL)(hr) (ng/mL) (hr)^(a) (hr)^(a) N 10 10 10 10 10 Geo- 46,865 17.5 2,5321.0 0.29 metric Mean SD 11,965 5.25 607 0.5-2.5 0.20-0.61 ^(a)T_(max)and T_(thera) present the value as a median or a range.

Rizatriptan was rapidly absorbed after oral administration ofmeloxicam/rizatriptan, with a T_(max) of 0.64 hour (38 min), whichcompares to 0.88 hour for the same dose of standard rizatriptan(Maxalt®) (FIG. 13 and Table 9). Systemic exposure measured usingC_(max) and AUC were also numerically greater for rizatriptan afteradministration of meloxicam/rizatriptan versus standard rizatriptan.

TABLE 9 Rizatriptan Pharmacokinetic Parameters for Meloxicam/Rizatriptanand Standard Rizatriptan AUC_(0-inf) T_(1/2) el C_(max) T_(max)Statistic (pg · hr/mL) (hr) (ng/mL) (hr)^(a) Meloxicam/ N 10 10 10 10Rizatriptan Geo- 83,800 1.98 29,991 0.64 (20 mg meloxicam/ metric 10 mgrizatriptan) Mean SD 22,787 0.28 11,041 0.5-2.5 Standard Rizatriptan N10 10 10 10 (Maxalt ®) (10 mg Geo- 71,811 1.81 23,236 0.88 rizatriptan)metric Mean SD 24,287 0.11 9,476 0.5-2 ^(a)T_(max) presents the value asa median or a range.

Meloxicam/rizatriptan was well tolerated with no relevant differences insafety profile between the two treatment arms. There were no seriousadverse events in the study.

Example 7

A Phase 3, randomized, double-blind, multicenter, active- andplacebo-controlled trial is carried out to assess the efficacy andsafety of meloxicam/rizatriptan in the acute treatment of moderate andsevere migraine, in patients with a history of inadequate response toprior acute migraine treatments. Eligible patients are randomized in a2:2:2:1 ratio to treatment with meloxicam/rizatriptan (20 mgmeloxicam/10 mg rizatriptan, with SBEβCD and sodium bicarbonate asdescribed in Example 4 above), rizatriptan (10 mg) (rizatriptan arm),meloxicam (20 mg) with SBEβCD and sodium bicarbonate (meloxicam arm), orplacebo. Co-primary endpoints are freedom from headache pain, andfreedom from the most bothersome migraine-associated symptom (nausea,photophobia, or phonophobia), two hours after dosing, formeloxicam/rizatriptan as compared to placebo.

Superiority of meloxicam/rizatriptan to the rizatriptan and themeloxicam arms (component contribution) will be established based onsustained freedom from headache pain from 2 hours to 24 hours afterdosing (key secondary endpoint).

Eligible patients must have a history of inadequate response to prioracute migraine treatments, assessed using the Migraine TreatmentOptimization Questionnaire (mTOQ-4). The mTOQ-4 is a validatedquestionnaire that assesses efficacy response to prior acute treatmentsbased on four aspects (two-hour pain freedom, efficacy for at least 24hours with one dose, ability to plan daily activities, and disruption ofdaily activities).

It is expected that meloxicam/rizatriptan will show significantimprovement over placebo and superiority over the rizatriptan and themeloxicam arms because of the rapid absorption and distinct dualmechanisms of action of meloxicam/rizatriptan described herein.

Example 8

A female migraine sufferer visits her physician in the hope of havingrelief from her migraine pain. Her doctor gives her 10 mg rizatriptan(Maxalt®), which she takes during her next acute migraine. It providessome relief of pain, nausea, allodynia, such as cutaneous allodynia,photophobia, and phonophobia, but not complete relief from thesesymptoms. On her next visit, her doctor gives her 20 mg of meloxicam ina tablet also containing SBEβCD and 500 mg of sodium bicarbonate, whichshe takes during her next acute migraine. It provides some relief ofpain, nausea, allodynia, such as cutaneous allodynia, photophobia, andphonophobia, but not complete relief from these symptoms. On her nextvisit, her doctor gives her a tablet described in Example 4 above. Shereports that at 2 hours and 24 hours after taking the tablet, she hasabout 10-30% improvement in pain, nausea, allodynia, such as cutaneousallodynia, photophobia, and/or phonophobia over what she experiencedafter taking meloxicam or rizatriptan alone.

Example 9

A male migraine sufferer visits his physician in the hope of havingrelief from his migraine pain. His doctor gives him 10 mg rizatriptan(Maxalt®), which he takes during his next acute migraine. It providessome relief of pain, nausea, allodynia, such as cutaneous allodynia,photophobia, and phonophobia, but not complete relief from thesesymptoms. On his next visit, his doctor gives his 20 mg of meloxicam ina tablet also containing SBEβCD and 500 mg of sodium bicarbonate, whichhe takes during his next acute migraine. It provides some relief ofpain, nausea, allodynia, such as cutaneous allodynia, photophobia, andphonophobia, but not complete relief from these symptoms. On his nextvisit, his doctor gives him a tablet described in Example 4 above. Hereports that at 2 hours and 24 hours after taking the tablet, he hasabout 30-60% improvement in pain, nausea, allodynia, such as cutaneousallodynia, photophobia, and/or phonophobia over what he experiencedafter taking meloxicam or rizatriptan alone.

Example 10

A female migraine sufferer visits her physician in the hope of havingrelief from her migraine pain. Her doctor gives her 10 mg rizatriptan(Maxalt®), which she takes during her next acute migraine. It providessome relief of pain, nausea, allodynia, such as cutaneous allodynia,photophobia, and phonophobia, but not complete relief from thesesymptoms. On her next visit, her doctor gives her 20 mg of meloxicam ina tablet also containing SBEβCD and 500 mg of sodium bicarbonate, whichshe takes during her next acute migraine. It provides some relief ofpain, nausea, allodynia, such as cutaneous allodynia, photophobia, andphonophobia, but not complete relief from these symptoms. On her nextvisit, her doctor gives her a tablet described in Example 4 above. Shereports that at 2 hours and 24 hours after taking the tablet, she hasabout 60-100% improvement in pain, nausea, allodynia, such as cutaneousallodynia, photophobia, and/or phonophobia over what she experiencedafter taking meloxicam or rizatriptan alone.

Example 11

Over 37 million Americans suffer from migraine according to the Centersfor Disease Control, and it is the leading cause of disability amongneurological disorders in the United States according to the AmericanMigraine Foundation. Migraine is characterized by recurrent attacks ofpulsating, often severe and disabling head pain associated with nausea,and sensitivity to light and or sound. It is estimated that migraineaccounts for $78 billion in direct (e.g. doctor visits, medications) andindirect (e.g. missed work, lost productivity) costs each year in theUnited States [Gooch C L, Pracht E, Borenstein A R, The burden ofneurological disease in the United States: A summary report and call toaction. Ann Neurol. 2017 April; 81(4):479-484]. Published surveys ofmigraine sufferers indicate that more than 70% are not fully satisfiedwith their current treatment, that nearly 80% would try a new therapy,and that they desire treatments that work faster, more consistently, andresult in less symptom recurrence [(1) Smelt A F, Louter M A, Kies D A,Blom J W, Terwindt G M, van der Heijden G J, De Gucht V, Ferrari M D,Assendelft W J, What do patients consider to be the most importantoutcomes for effectiveness studies on migraine treatment? Results of aDelphi study. PLoS One. 2014 Jun. 16; 9(6):e98933, 6; and (2) Lipton RB, Stewart W F, Acute migraine therapy: do doctors understand whatpatients with migraine want from therapy? Headache. 1999; 39(suppl2):S20-S26].

The World Health Organization classifies severe migraine attacks asamong the most disabling illnesses, comparable to dementia, quadriplegiaand active psychosis [(1) Menken et al. Arch Neurol. 2000; 57:418-420;and (2) Shapiro and Goadsby. Cephalalgia. 2007; 27:991-4]. Debilitatingpain, and the often-constant fear of the next migraine attack, damagefamily life, social life, and employment [Global Burden of DiseaseStudy. Lancet. 2017; 390:1211-1259]. Depression and anxiety are twice ascommon in people with migraine than in healthy individuals [Antonaci etal. J Headache Pain. 2011; 12:115-125]. Widespread misperception of theseriousness of migraine contributes to its under-recognition andunder-treatment [Global Burden of Disease Study. Lancet. 2017;390:1211-1259]. The majority of patients are not fully satisfied withtheir current treatment. Thus, there is an urgent need for newtreatments that provide improved efficacy for this serious neurologicaldisease.

A Phase 3, randomized, double-blind, multicenter, placebo- andactive-controlled trial was conducted to assess the efficacy and safetyof the combination of meloxicam and rizatriptan (meloxicam/rizatriptan)in the acute treatment of moderate and severe migraine. Eligiblepatients must have an age of 18 to 65 years, an established diagnosis(at least 1 year) of migraine with or without aura as defined by ICHD-3criteria, an average of 2 to 8 moderate to severe migraines per month,had a history of inadequate response to prior acute migraine treatments,assessed by a score of 7 using the Migraine Treatment OptimizationQuestionnaire (mTOQ-4) (the average score was 3.6), corresponding topoor response to prior acute treatments. Exclusion criteria includedcluster headaches or other types of migraines, chronic daily headache 15non-migraine headache days per month), history of significantcardiovascular disease, and uncontrolled hypertension. In addition to ahistory of inadequate response, enrolled patients exhibited a high rateof characteristics that are strongly associated with poor treatmentoutcomes including cutaneous allodynia (75.4%), severe migraine painintensity (41.2%), obesity (43.7%), and morning migraine (36.6%). Atotal of 1,594 patients were randomized in a 2:2:2:1 ratio to themonolayer tablet of Example 4 (20 mg meloxicam/10 mg rizatriptan, withSBEβCD and sodium bicarbonate), rizatriptan (10 mg), meloxicam (20 mg)with SBEβCD (MoSEIC Meloxicam), or placebo, to treat a single migraineattack of moderate or severe intensity. The two co-primary endpoints ofthe trial were the proportion of patients who are free from headachepain two hours after dosing, and the proportion of patients who nolonger suffered from their most bothersome migraine-associated symptom(nausea, photophobia, or phonophobia) two hours after dosing, formeloxicam/rizatriptan as compared to placebo. Superiority ofmeloxicam/rizatriptan to the rizatriptan and meloxicam arms (componentcontribution) was to be established based on sustained freedom fromheadache pain from two to 24 hours after dosing (key secondaryendpoint). The study was conducted pursuant to an FDA Special ProtocolAssessment (SPA). Rizatriptan, an active comparator in the trial, isconsidered to be the fastest acting oral triptan and one of the mosteffective medications currently available for the acute treatment ofmigraine. (Ferrari M D, Roon K I, Lipton R B, Goadsby Pi. Oral triptans(serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: ameta-analysis of 53 trials. Lancet. 2001 Nov. 17; 358(9294):1668-75.)

Meloxicam/rizatriptan provided rapid relief of migraine pain with thepercentage of patients achieving pain relief with meloxicam/rizatriptanbeing numerically greater than with rizatriptan at every time pointmeasured starting at 15 minutes, and statistically significant by 60minutes (p=0.04) (FIG. 14). The proportions of patients experiencingpain relief 1.5 hours after dosing were 60.5% for meloxicam/rizatriptancompared to 52.5% for rizatriptan and 48.3% for placebo (p=0.019,p=0.04, respectively versus meloxicam/rizatriptan) (FIG. 14).

Meloxicam/rizatriptan met the two regulatory co-primary endpoints bydemonstrating, with high statistical significance, a greater percentageof patients as compared to placebo achieving pain freedom (19.9% versus6.7%, p<0.001, FIG. 15), and absence of most bothersome symptom (36.9%versus 24.4%, p=0.002), 2 hours after dosing.

Superiority of meloxicam/rizatriptan to rizatriptan (active comparatorand MoSEIC™ meloxicam (component contribution) was established asspecified in the SPA, by the demonstration of a greater percentage ofpatients receiving meloxicam/rizatriptan achieving sustained painfreedom from 2 hours to 24 hours after dosing, compared to rizatriptan,MoSEIC™ meloxicam, and placebo (16.1%, 11.2%, 6.8% and 5.3%,respectively; p=0.038, p=0.001, and p<0.001, respectively versusmeloxicam/rizatriptan, FIG. 16A), the pre-specified key secondaryendpoint to demonstrate component contribution. About 80% of thepatients treated with meloxicam/rizatriptan who achieved pain freedom at2 hours maintained pain freedom through 24 hours. These resultsdemonstrated the significant improvement in pain freedom and superiorityof meloxicam/rizatriptan to rizatriptan in treating migraine.

Meloxicam/rizatriptan provided substantially greater and more sustainedmigraine pain relief compared to placebo and rizatriptan, whichtranslated to a significant reduction in rescue medication use formeloxicam/rizatriptan compared to placebo and rizatriptan. Thepercentage of patients experiencing sustained pain relief from 2 hoursto 24 hours after dosing was 53.3% for meloxicam/rizatriptan, comparedto 33.5% for placebo and 43.9% for rizatriptan (p<0.001, p=0.006,respectively versus meloxicam/rizatriptan) (FIG. 16B).

Sustained pain relief from 2 hours to 48 hours was also experienced by astatistically significantly greater proportion of meloxicam/rizatriptanpatients (46.5%), compared to placebo (31.1%) and rizatriptan (36.5%)patients (p<0.001, p=0.003, respectively versus meloxicam/rizatriptan)(FIG. 17B). The sustained pain freedom from 2 hours to 48 hours was alsoexperienced by a statistically significantly greater proportion ofmeloxicam/rizatriptan patients (15.4%), compared to placebo (5.3%), andrizatriptan (8.8%), and MoSEIC™ meloxicam (8.1%) patients (p<0.001,p=0.003, p=<0.001, respectively versus meloxicam/rizatriptan) (FIG.17A). About 77% of patients treated with meloxicam/rizatriptan whoachieved pain freedom at 2 hours maintained the pain freedom through 48hours.

Rescue medication was used by 23.0% patients receivedmeloxicam/rizatriptan, compared to 43.5% patients received placebo and34.7% patients received rizatriptan (p<0.001 for each group versusmeloxicam/rizatriptan) (FIG. 18). About 77% of patients receivingmeloxicam/rizatriptan did not require rescue medication. These resultsdemonstrated the superiority of meloxicam/rizatriptan to rizatriptan, anactive comparator, in treating migraine.

Meloxicam/rizatriptan was statistically significantly superior torizatriptan on several other secondary endpoints, including PatientGlobal Impression of Change (PGI-C) (p=0.022), and return to normalfunctioning at 24 hours (p=0.027).

Some of the p-values for meloxicam/rizatriptan versus rizatriptan forvarious endpoints are listed in Table 10 below, demonstrating thestatistically significant superiority of meloxicam/rizatriptan overrizatriptan in treating migraine.

TABLE 10 P-Values for Meloxicam/Rizatriptan vs Rizatriptan for VariousEndpoints P-value Endpoint Meloxicam/Rizatriptan vs Rizatriptan 1 hourPain Relief 0.04 2-24 hour Sustained Pain Relief 0.006 2-48 hourSustained Pain Relief 0.003 2-24 hour Sustained Pain Freedom 0.038 2-48hour Sustained Pain Freedom 0.003 PGI-C 0.022 Functional Improvement0.027 at 24 hours Use of Rescue Medication <0.001

Given that Rizatriptan, an active comparator in the trial, is consideredto be the fastest acting oral triptan and one of the most effectivemedications currently available for the acute treatment of migraine, andthat this trial enrolled patients with difficult-to-treat migraine, theobserved treatment effects with meloxicam/rizatriptan that providedgreater and more lasting migraine pain relief than rizatriptan, ishighly significant. Many patients experience a suboptimal response totheir current acute migraine treatments, placing them at increased riskof headache related disability and progression to chronic migraine,factors associated with increased healthcare costs. The results of thisstudy suggest that meloxicam/rizatriptan may provide an importanttreatment option for people with difficult-to-treat migraine.

Meloxicam/rizatriptan was safe and well tolerated in the patientsstudied in the trial. The most commonly reported adverse events withmeloxicam/rizatriptan were nausea, dizziness and somnolence, none ofwhich occurred at a rate greater than placebo or greater than 3%. Therewas one serious adverse event in the meloxicam/rizatriptan arm which wasdeemed by the investigator not to be related to the study drug.

The results of this trial demonstrate the ability ofmeloxicam/rizatriptan to provide unique benefits to migraine patients,with fast, strong, and durable relief of migraine pain as compared to apotent active comparator, rizatriptan, in a stringently designed trialenriched with patients with difficult-to-treat migraine. These resultshave potentially important implications for patient care based on thehigh rate of inadequate response to and patient dissatisfaction withcurrent treatments.

Meloxicam/rizatriptan incorporates multiple mechanisms of action toaddress various migraine processes with the goal of providing enhancedeffectiveness. Meloxicam/rizatriptan is thought to act by inhibitingCGRP release, reversing CGRP-mediated vasodilation, and inhibitingneuro-inflammation, pain signal transmission, and central sensitization.The results of this trial validate this approach, demonstrating thatmeloxicam/rizatriptan can provide significant benefit that is greaterthan that of currently available treatments, even in patients withdifficult-to-treat migraine. Meloxicam/rizatriptan may be used for theacute treatment of migraine in adults with or without aura effectively.

Example 12

Meloxicam/rizatriptan is also being evaluated in another Phase 3 trialwhich is a randomized, double-blind, placebo-controlled study evaluatingthe early treatment of migraine with meloxicam/rizatriptan. In contrastto this ongoing trial in which patients with a history of inadequateresponse treated migraine attacks once they have developed moderate orsevere intensity of migraine, in the other trial, patients are toadminister meloxicam/rizatriptan at the earliest sign of migraine pain.

Eligible patients are randomized in a 1:1 ratio to treatment withmeloxicam/rizatriptan (20 mg meloxicam/10 mg rizatriptan, with SBEβCDand sodium bicarbonate as described in Example 4 above), or placebo.Adult subjects with an established diagnosis of migraine with or withoutaura. The treatment with meloxicam/rizatriptan is initiated at the firstsign of migraine pain onset.

Co-primary endpoints are freedom from headache pain, and freedom fromthe most bothersome migraine-associated symptom (nausea, photophobia, orphonophobia), two hours after dosing, for meloxicam/rizatriptan ascompared to placebo.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as amounts, percentage, and so forth usedin the specification and claims are to be understood in all instances asindicating both the exact values as shown and as being modified by theterm “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the specification and attached claimsare approximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the embodiments (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate theembodiments and does not pose a limitation on the scope of any claim. Nolanguage in the specification should be construed as indicating anynon-claimed element essential to the practice of the claims.

Groupings of alternative elements or embodiments disclosed herein arenot to be construed as limitations. Each group member may be referred toand claimed individually or in any combination with other members of thegroup or other elements found herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or to expedite prosecution. When any suchinclusion or deletion occurs, the specification is deemed to contain thegroup as modified thus fulfilling the written description of all Markushgroups if used in the appended claims.

Certain embodiments are described herein, including the best mode knownto the inventors for carrying out the claimed embodiments. Of course,variations on these described embodiments will become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventor expects skilled artisans to employ such variations asappropriate, and the inventors intend for the claimed embodiments to bepracticed otherwise than specifically described herein. Accordingly, theclaims include all modifications and equivalents of the subject matterrecited in the claims as permitted by applicable law. Moreover, anycombination of the above-described elements in all possible variationsthereof is contemplated unless otherwise indicated herein or otherwiseclearly contradicted by context.

In closing, it is to be understood that the embodiments disclosed hereinare illustrative of the principles of the claims. Other modificationsthat may be employed are within the scope of the claims. Thus, by way ofexample, but not of limitation, alternative embodiments may be utilizedin accordance with the teachings herein. Accordingly, the claims are notlimited to embodiments precisely as shown and described.

The invention claimed is:
 1. A method of relieving migraine pain,comprising: orally administering to a human being in need thereof, acombination of: 1) a complex of a meloxicam and asulfobutylether-β-cyclodextrin, 2) a bicarbonate, and 3) a rizatriptan,wherein the combination is orally administered when the human being issuffering from severe migraine pain of an acute migraine, wherein twohours after the combination is orally administered, the human beingexperiences a greater reduction in migraine pain than the human beingwould experience two hours after the same amount of the meloxicam isorally administered alone.
 2. The method of claim 1, wherein two hoursafter the combination is orally administered, the human beingexperiences a greater reduction in migraine pain than the human beingwould experience two hours after the same amount of the rizatriptan isorally administered alone.
 3. The method of claim 1, wherein two hoursafter the combination is orally administered, the human beingexperiences a greater reduction in the human being's most bothersomesymptom than the human being would experience two hours after the sameamount of the rizatriptan is orally administered alone, wherein the mostbothersome symptom is nausea, phonophobia, or photophobia.
 4. The methodof claim 1, wherein at 2 hours after the combination is orallyadministered, the human being experiences a greater reduction inmigraine pain than the human being would experience 2 hours after thesame amount of the rizatriptan is orally administered alone, and at 24hours after the combination is orally administered, the human beingexperiences a greater reduction in migraine pain than the human beingwould experience 24 hours after the same amount of the rizatriptan isorally administered alone.
 5. The method of claim 1, wherein the humanbeing has a history of inadequate response to prior migraine treatments.6. The method of claim 1, wherein the human being is selected for havinga history of inadequate response to prior migraine treatments.
 7. Themethod of claim 1, wherein the human being has had an average of about 2to about 8 severe migraine attacks per month.
 8. The method of claim 1,wherein the human being is selected for having an average of about 2 toabout 8 severe migraine attacks per month.
 9. The method of claim 1,wherein 1) the complex of the meloxicam and thesulfobutylether-β-cyclodextrin, 2) the bicarbonate, and 3) therizatriptan, are combined together in a monolayer tablet.
 10. The methodof claim 1, wherein the combination contains: about 10 mg of rizatriptanin the free base form or a molar equivalent of a salt form; about 20 mgof meloxicam in the free base form, or a molar equivalent of a saltform; and about 400 mg to about 600 mg of the bicarbonate.
 11. Themethod of claim 10, wherein the bicarbonate is sodium bicarbonate. 12.The method of claim 10, wherein 30 minutes after the combination isorally administered, the human being experiences a greater reduction inmigraine pain than the human being would experience 30 minutes after thesame amount of the rizatriptan is orally administered alone.
 13. Themethod of claim 12, wherein the human being has a history of inadequateresponse to prior migraine treatments.
 14. The method of claim 12,wherein the human being is selected for having a history of inadequateresponse to prior migraine treatments.
 15. The method of claim 12,wherein 1) the complex of the meloxicam and thesulfobutylether-β-cyclodextrin, 2) the bicarbonate, and 3) therizatriptan, are combined together in a monolayer tablet.
 16. The methodof claim 12, wherein at 2 hours after the combination is orallyadministered, the human being experiences a greater reduction inmigraine pain than the human being would experience 2 hours after thesame amount of the rizatriptan is orally administered alone, and at 24hours after the combination is orally administered, the human beingexperiences a greater reduction in migraine pain than the human beingwould experience 24 hours after the same amount of the rizatriptan isorally administered alone.
 17. The method of claim 1, wherein the humanbeing does not take any rescue medication for at least 24 hours afterthe combination is orally administered.
 18. The method of claim 1,wherein the human being achieves pain freedom at 2 hours after thecombination is orally administered.
 19. The method of claim 1, whereinthe human being achieves absence of the most bothersome symptom to thehuman being at 2 hours after the combination is orally administered,wherein the most bothersome symptom is nausea, phonophobia, orphotophobia.
 20. The method of claim 1, wherein the complex of themeloxicam and the sulfobutylether-β-cyclodextrin are present in a dosageform with the bicarbonate, and the bicarbonate is present in an amountthat is effective to increase the dissolution rate of meloxicam.
 21. Themethod of claim 1, wherein the human being has migraine pain that isaccompanied with nausea.
 22. The method of claim 21, wherein at 2 hoursafter the combination is orally administered, the human beingexperiences a greater reduction in nausea than the human being wouldexperience 2 hours after the same amount of the rizatriptan is orallyadministered alone.
 23. The method of claim 1, wherein the bicarbonateis sodium bicarbonate.
 24. The method of claim 1, wherein the meloxicamis in the free base form.
 25. The method of claim 1, wherein therizatriptan is rizatriptan benzoate.
 26. The method of claim 1, whereinthe complex of the meloxicam and the sulfobutylether-β-cyclodextrin, thebicarbonate, and the rizatriptan are present in a single dosage form.27. The method of claim 1, wherein migraine pain is accompanied bydisturbed vision.
 28. The method of claim 27, wherein the human beingachieves absence of the disturbed vision at 2 hours after thecombination is orally administered.